Functionalized long-chain hydrocarbon mono- and di-carboxylic acids and their use for the prevention or treatment of disease

ABSTRACT

This invention provides compounds of Formulae (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), (IL), (II), (III), (IIIA), and (IIIB); pharmaceutically acceptable salts and solvates thereof; and compositions thereof. This invention further provides methods for treating a disease, including but not limited to, liver disease or an abnormal liver condition; cancer (such as hepatocellular carcinoma or cholangiocarcinoma); a malignant or benign tumor of the lung, liver, gall bladder, bile duct or digestive tract; an intra- or extra-hepatic bile duct disease; a disorder of lipoprotein; a lipid-and-metabolic disorder; cirrhosis; fibrosis; a disorder of glucose metabolism; a cardiovascular or related vascular disorder; a disease resulting from steatosis, fibrosis, or cirrhosis; a disease associated with increased inflammation (such as hepatic inflammation or pulmonary inflammation); hepatocyte ballooning; a peroxisome proliferator activated receptor-associated disorder; an ATP citrate lyase disorder; an acetyl-coenzyme A carboxylase disorder; obesity; pancreatitis; or renal disease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/878,852, filed Jul. 26, 2019, and U.S. Provisional Application No.62/901,739, filed Sep. 17, 2019, the disclosure of each of which isincorporated by reference herein in its entirety.

FIELD OF THE INVENTION

This invention provides compounds of Formulae (IA), (IB), (IC), (ID),(IE), (IF), (IG), (IH), (IJ), (IK), (IL), (II), (III), (IIIA), and(IIIB), and pharmaceutically acceptable salts and solvates thereof, andcompositions thereof. This invention further provides methods forpreventing or treating a disease, including but not limited to, liverdisease or an abnormal liver condition; cancer (such as hepatocellularcarcinoma or cholangiocarcinoma); a malignant or benign tumor of thelung, liver, gall bladder, bile duct or digestive tract; an intra- orextra-hepatic bile duct disease; a disorder of lipoprotein; alipid-and-metabolic disorder; cirrhosis; fibrosis; a disorder of glucosemetabolism; a cardiovascular or related vascular disorder; a diseaseresulting from steatosis, fibrosis, or cirrhosis; a disease associatedwith increased inflammation (such as hepatic inflammation or pulmonaryinflammation); hepatocyte ballooning; a peroxisome proliferatoractivated receptor-associated disorder; an ATP citrate lyase disorder;an acetyl-coenzyme A carboxylase disorder; obesity; pancreatitis; orrenal disease.

BACKGROUND OF THE INVENTION

Hepatocellular carcinoma (HCC) is one of the most common primary livermalignancies. Patients with chronic liver disease, such as livercirrhosis and fibrosis, are at increased risk for development of HCC.Thus, patients with chronic liver diseases should be closely monitoredfor development of HCC. Risk factors for HCC include cirrhosis,non-alcoholic fatty liver disease (NAFLD), nonalcoholic stetohepatitis(NASH), chronic alcohol consumption, hepatitis B, and hepatitis C, typelib hyperlipidemia, mixed dyslipidemia, obesity, and type 2 diabetes.

Type IIb hyperlipidemia patients have a high risk of developing NAFLDand non-alcoholic steatosis hepatitis (NASH), which can develop due tohepatic triglyceride overproduction and accumulation. Elevated levels oflow-density lipoprotein cholesterol (LDL-C) and triglycerides areassociated with mixed dyslipidemia, including type lib hyperlipidemiawhich is characterized by elevation of apolipoprotein B, verylow-density lipoprotein cholesterol (VLDL-C), intermediate densitylipoprotein cholesterol (DDL), and small dense low-density lipoprotein(LDL) levels, in addition to elevation in LDL-C and triglyceride levels.

Current treatment options for treatment of type lib hyperlipidemia arelimited. While statins can be effective for lowering LDL-C and reducinginflammation, they are generally not very effective for loweringtriglyceride concentrations. Further, high dose statin therapy is oftennot well tolerated because it can cause muscle pain (myalgia) andincrease a patient's risk of serious muscle toxicity, such asrhabdomyolysis. Also, commonly used triglyceride-lowering agents thatare administered in combination with statins are often notwell-tolerated. When administered with statins, fibrates are known tohave drug-drug interactions, resulting in increased statin blood druglevels, myalgia, an increased risk of muscle toxicity and an increasedsafety risk. Indeed, the interaction of the statin Baychol(cerivastatin) with the fibrate gemfibrozil resulted in severe muscletoxicity and deaths and raised safety concerns that resulted in theremoval of Baychol from the U.S. market. Fish oil, which has been usedto lower triglyceride levels, needs to be taken multiple times daily andcan cause a fish oil aftertaste, burping or regurgitation. Niacin causesflushing, particularly when administered in combination with statins.

Hepatocellular adenomas are benign liver neoplasms whose genetics andpathophysiology are not entirely known. These lesions pose diagnosticand therapeutic challenges and treatments post-exeresis are stillchallenging. Bile duct adenomas raise the same therapeutic challenges.Digestive system adenomas are sporadic neoplasms, arising from theglandular epithelium of the stomach, small intestine, biliary tract,colon, and rectum.

Gastrointestinal (digestive) cancers are cancers that affect thegastrointestinal tract and other organs that are contained within thedigestive system. Gastrointestinal stromal tumor (GIST), is a rare typeof sarcoma that forms along the gastrointestinal tract, but mostlystarts in the stomach or small intestine. The origins of the digestivecancers were linked strongly to chronic inflammation of the organs thatdevelop through a series of histopathologic stages dependent of theorgan affected. For cancers of the gastrointestinal tract or GIST,surgery will likely be recommended to remove the tumor and/or to helpmaintain normal function. Other treatment options are radiotherapy,chemotherapy, hormone therapy, or targeted therapies.

Thus, there is a need for a safe and effective therapy for treatment orprevention of cancer (such as gastrointestinal cancer, hepatocellularcarcinoma or cholangiocarcinoma); a malignant or benign tumor of thelung, liver, gall bladder, bile duct or digestive tract; liver diseaseor an abnormal liver condition, an intra- or extra-hepatic bile ductdisease; a disorder of lipoprotein; a lipid-and-metabolic disorder;cirrhosis; fibrosis; a disorder of glucose metabolism; a cardiovascularor related vascular disorder; a disease resulting from steatosis,fibrosis, or cirrhosis; a disease associated with increased inflammation(such as hepatic inflammation or pulmonary inflammation); hepatocyteballooning; a peroxisome proliferator activated receptor-associateddisorder; an ATP citrate lyase disorder; an acetyl-coenzyme Acarboxylase disorder; obesity; pancreatitis; or renal disease.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formulae (IA), (IB), (IC),(ID), (IE), (IF), (IG), (IH), (IJ), (IK), (IL), (II), (III), (IIIA), and(IIIB), and pharmaceutically acceptable salts and solvates thereof (eachcompound, pharmaceutically acceptable salt and solvate being a “compoundof the invention”).

The present invention also provides compositions comprising i) aneffective amount of a compound of the invention and ii) apharmaceutically acceptable carrier or vehicle (each composition being a“composition of the invention”).

The present invention further provides methods for treating orpreventing a disease, comprising administering to a subject in needthereof an effective amount of a compound of the invention, wherein thedisease is liver disease or an abnormal liver condition; cancer (such ashepatocellular carcinoma or cholangiocarcinoma); a malignant or benigntumor of the lung, liver, gall bladder, bile duct or digestive tract; anintra- or extra-hepatic bile duct disease; a disorder of lipoprotein; alipid-and-metabolic disorder; cirrhosis; fibrosis; a disorder of glucosemetabolism; a cardiovascular or related vascular disorder; a diseaseresulting from steatosis, fibrosis, or cirrhosis; a disease associatedwith increased inflammation (such as hepatic inflammation or pulmonaryinflammation); hepatocyte ballooning; a peroxisome proliferatoractivated receptor-associated disorder; an ATP citrate lyase disorder;an acetyl-coenzyme A carboxylase disorder; obesity; pancreatitis; orrenal disease.

The present invention further provides methods for treating orpreventing a disease, wherein the disease is cancer, alipid-and-metabolic disorder, a liver disorder, cirrhosis, fibrosis, adisorder of glucose metabolism, a peroxisome proliferator activatedreceptor-associated disorder, a malignant or benign tumor of the lung,liver, bile and digestive tract, an ATP citrate lyase disorder, anacetyl-coenzyme A carboxylase disorder, obesity, pancreatitis, renaldisease, hepatocyte ballooning, hepatic inflammation, or pulmonaryinflammation.

The present invention further provides methods for reducing in asubject's blood plasma or blood serum, the subject's C-reactive protein(CRP) concentration, serum amyloid A (SAA) concentration, alanineaminotransferase (ALT) concentration, aspartate aminotransferase (AST)concentration, alkaline phosphatase (ALP) concentration, gamma-glutamyltransferase (GGT) concentration, serum creatinine concentration,7α-hydroxy-4-cholesten-3-one (C4) concentration, protein:creatinineratio, creatine kinase concentration, angiopoietin-like protein 3concentration, angiopoietin-like protein 4 concentration,angiopoietin-like protein 8 concentration, fibrinogen concentration,total cholesterol concentration, low-density lipoprotein cholesterolconcentration, low-density lipoprotein concentration, very low-densitylipoprotein cholesterol concentration, very low-density lipoproteinconcentration, non-HDL cholesterol concentration, non-HDL concentration,apolipoprotein B concentration, lipoprotein(a) concentration, or serumtriglyceride concentration, comprising administering to a subject inneed thereof an effective amount of a compound of the invention.

The present invention further provides methods for reducing triglycerideconcentration in a subject's liver, comprising administering to asubject in need thereof an effective amount of a compound of theinvention.

The present invention further provides methods for elevating in asubject's blood plasma or blood serum a concentration of high-densitylipoprotein cholesterol or high-density lipoprotein, comprisingadministering to a subject in need thereof an effective amount of acompound of the invention.

The present invention further provides methods for treating a disease,comprising administering to a subject in need thereof an effectiveamount of a compound of the invention, wherein the disease isgastrointestinal disease, irritable bowel syndrome (IBS), inflammatorybowel disease (IBD), or autoimmune disease.

The present invention further provides methods for regressing, reducingthe rate of progression, or inhibiting progression, of fibrosis,hepatocyte ballooning or hepatic inflammation, comprising administeringto a subject in need thereof an effective amount of a compound of theinvention.

The present invention further provides methods for inhibiting, reducing,or delaying advancement of a subject's lipid synthesis, liver steatosis,hepatocyte ballooning or inflammation, liver fibrosis, lung fibrosis, orcirrhosis, comprising administering to a subject in need thereof aneffective amount of a compound of the invention.

The present invention further provides methods for reducing a subject'srisk of developing or having atherosclerosis, coronary heart disease,peripheral vascular disease, stroke, or restenosis, comprisingadministering to a subject in need thereof an effective amount of acompound of the invention.

The present invention further provides methods for elevating HDLconcentration in a subject's blood serum or plasma, comprisingadministering to a subject in need thereof an effective amount of acompound of the invention.

The present invention further provides methods for inhibiting NF-kB orstellate cell activation, comprising administering to a subject in needthereof an effective amount of a compound of the invention.

The present invention further provides methods for activating PPAR(peroxisome proliferator-activated receptor), comprising administeringto a subject in need thereof an effective amount of a compound of theinvention.

The present invention further provides methods for reducing the fat orcholesterol content of livestock meat or poultry eggs, comprisingadministering to the livestock or poultry an effective amount of acompound of the invention.

The present invention further provides methods for modulating, directlyinhibiting or allosterically inhibiting ATP citrate lyase in a subject,comprising administering to a subject in need thereof an effectiveamount of a compound of the invention.

The present invention further provides methods for modulating, directlyinhibiting or allosterically inhibiting acetyl-CoA carboxylase 1 oracetyl-CoA carboxylase 2 in a subject, comprising administering to asubject in need thereof an effective amount of a compound of theinvention.

The present invention further provides method for treating or preventinga disease, comprising administering to a subject in need thereof aneffective amount of a composition of the invention, wherein the diseaseis cancer, a lipid-and-metabolic disorder, a liver disorder, cirrhosis,fibrosis, a disorder of glucose metabolism, a peroxisome proliferatoractivated receptor-associated disorder, a malignant or benign tumor ofthe lung, liver, bile and digestive tract, an ATP citrate lyasedisorder, an acetyl-coenzyme A carboxylase disorder, obesity,pancreatitis, renal disease, hepatocyte ballooning, hepaticinflammation, or pulmonary inflammation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1D show inhibitory effects of Compounds I-32, I-61, I-1, andIII-1, respectively, on mouse primary hepatocyte lipogenesis as percentcontrol.

FIGS. 2A-2D show anti-proliferative effects of Compounds I-32, I-61,I-1, and III-1, respectively, on Hepa1-6 cells as a percent of vehiclecontrol.

FIGS. 3A-3D show anti-proliferative effects of Compounds I-32, I-61,I-1, and III-1, respectively, on Hep3B cell proliferation as a percentof vehicle control.

FIGS. 4A-4D show anti-clonogenic effects of Compounds I-32, I-61, I-1,and III-1, respectively, in Hepa1-6 cells as a percent of vehiclecontrol.

FIGS. 5A-5D show anti-clonogenic effects of Compounds I-32, I-61, I-1,and III-1, respectively, in Hep3B cells as a percent of vehicle control.

FIG. 6A shows anti-proliferation effects of Compound I-32 and sorafenib,in the absence or presence of the other, in Hep3B cells. FIG. 6B showsanti-proliferation effects of Compound I-32 and lenvatinib, in theabsence or presence of the other, in Hep3B cells. FIG. 6C showsanti-proliferation effects of Compound I-61 and sorafenib, in theabsence or presence of the other, in Hep3B cells. FIG. 6D showsanti-proliferation effects of Compound 1-61 and lenvatinib, in theabsence or presence of the other, in Hep3B cells.

FIG. 7A shows anti-proliferation effects of Compound I-32 and sorafenib,in the absence or presence of the other, in Hepa1-6 cells. FIG. 7B showsanti-proliferation effects of Compound I-32 and lenvatinib, in theabsence or presence of the other, in Hepa1-6 cells. FIG. 7C showsanti-proliferation effects of Compound I-61 and sorafenib, in theabsence or presence of the other, in Hepa1-6 cells. FIG. 7D showsanti-proliferation effects of Compound 1-61 and lenvatinib, in theabsence or presence of the other, in Hepa1-6 cells.

FIG. 8A shows synergistic anti-proliferation effect of Compound I-32 andsorafenib in Hep3B cells. FIG. 8B shows synergistic anti-proliferationeffect of Compound I-32 and lenvatinib in Hep3B cells. FIG. 8C showssynergistic anti-proliferation effect of Compound I-61 and sorafenib inHep3B cells. FIG. 8D shows synergistic anti-proliferation effect ofCompound I-61 and lenvatinib in Hep3B cells.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The term “about” when immediately preceding a numerical value means ±upto 20% of the numerical value. For example, “about” a numerical valuemeans ±up to 20% of the numerical value, in some embodiments, ±up to19%, ±up to 18%, ±up to 17%, ±up to 16%, ±up to 15%, ±up to 14%, ±up to13%, ±up to 12%, ±up to 11%, ±up to 10%, ±up to 9%, ±up to 8%, ±up to7%, ±up to 6%, ±up to 5%, ±up to 4%, ±up to 3%, ±up to 2%, ±up to 1%,±up to less than 1%, or any other value or range of values therein.

Throughout the present specification, numerical ranges are provided forcertain quantities. These ranges comprise all subranges therein. Thus,the range “from 50 to 80” includes all possible ranges therein (e.g.,51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all valueswithin a given range may be an endpoint for the range encompassedthereby (e.g., the range 50-80 includes the ranges with endpoints suchas 55-80, 50-75, etc.).

The term “pharmaceutically acceptable salt” includes both an acid and abase addition salt. Pharmaceutically acceptable salts can be obtained byreacting the compound of the invention functioning as a base, with aninorganic or organic acid to form a salt, for example, salts ofhydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid,camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citricacid, formic acid, hydrobromic acid, benzoic acid, tartaric acid,fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc.Pharmaceutically acceptable salts can also be obtained by reacting acompound of the invention functioning as an acid, with an inorganic ororganic base to form a salt, for example, salts of sodium, potassium,lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese,aluminum, ammonia, isopropylamine, trimethylamine, etc. Those skilled inthe art will further recognize that pharmaceutically acceptable saltscan be prepared by reaction of the compounds of the invention with anappropriate inorganic or organic acid or base via any of a number ofknown methods.

The term “solvate” refers to a solvation complex. Solvates can be formedby solvation (the combination of solvent molecules with molecules orions of the compounds of the invention), or a solvate can be anaggregate that comprises a solute ion or molecule or a solventmolecules. The solvent can be water, in which case the solvate is ahydrate. Examples of hydrates include, but are not limited to, ahemihydrate, monohydrate, dihydrate, trihydrate, hexahydrate, etc. Thesolvate can be formed via hydration, including via absorption ofmoisture. A pharmaceutically acceptable salt can also be a solvate.Where a solvate is obtained via crystallization from a solvent, thesolvent can be an alcohol, such as methanol or ethanol; an aldehyde; aketone, such as acetone; or an ester, such as ethyl acetate.

The compounds of the invention can have one or more asymmetric centersand can thus be enantiomers, racemates, diastereomers, otherstereoisomers and mixtures thereof. The compounds of the inventioninclude all such possible isomers (including geometric isomers), as wellas their racemic and optically pure forms whether or not they arespecifically depicted herein. Optically active (+) and (−), (A)- and(S)-, or (D)- and (L)-isomers can be prepared using chiral synthons orchiral reagents, or resolved using conventional techniques, for example,chromatography and fractional crystallization. Conventional techniquesfor the preparation or isolation of individual enantiomers includechiral synthesis from a suitable optically pure precursor or resolutionof the racemate using, for example, chiral high pressure liquidchromatography (HPLC). When the compounds of the invention comprise anolefenic double bond or another center of geometric asymmetry, andunless specified otherwise, the compounds of the invention include bothE and Z geometric isomers. Likewise, the compounds of the inventioninclude all tautomeric forms.

An “effective amount” when used in connection with a compound of theinvention means an amount of the compound of the invention that, whenadministered to a subject is effective to treat or prevent the disease,alone or with another pharmaceutically active agent.

An “effective amount” when used in connection with anotherpharmaceutically active agent means an amount of the otherpharmaceutically active agent that is effective to treat or prevent thedisease, alone or in combination with a compound of the invention.

A “subject” is a human or non-human mammal, e.g., a bovine, horse,feline, canine, rodent, or non-human primate. The human can be a male orfemale, child, adolescent or adult. The female can be premenarcheal orpostmenarcheal.

“Mammal” includes a human, domestic animal such as a laboratory animal(e.g., mouse, rat, rabbit, monkey, dog, etc.) and household pet (e.g.,cat, dog, swine, cattle, sheep, goat, horse, rabbit), and anon-domestic, wild animal.

All weight percentages (i.e., “% by weight” and “wt. %” and w/w)referenced herein, unless otherwise indicated, are relative to the totalweight of the mixture or composition, as the case can be.

The terms below, as used herein, have the following meanings, unlessindicated otherwise:

“Halo”, “Hal”, or “halogen” refers to Br, Cl, F, or I.

“Alkyl” refers to a fully saturated, straight or branched hydrocarbonchain having from one to twelve carbon atoms, and which is attached toan atom by a single bond. Alkyls with a number of carbon atoms rangingfrom 1 to 12 are included. An alkyl group with 1 to 12 carbon atoms is aC₁-C₁₂ alkyl, an alkyl group with 1 to 10 carbon atoms is a C₁-C₁₀alkyl, an alkyl group with 1 to 6 carbon atoms is a C₁-C₆ alkyl and analkyl group with 1 to 5 carbon atoms is a C₁-C₅ alkyl. A C₁-C₅ alkylincludes C₅ alkyls, C₄ alkyls, C₃ alkyls, C₂ alkyls and C₁ alkyl (i.e.,methyl). A C₁-C₆ alkyl includes all moieties described above for C₁-C₅alkyls but also includes C₆ alkyls. A C₁-C₁₀ alkyl includes all moietiesdescribed above for C₁-C₅ alkyls and C₁-C₆ alkyls, but also includes C₇,C₈, C₉ and C₁₀ alkyls. Similarly, a C₁-C₁₂ alkyl includes all theforegoing moieties, but also includes Cn and C₁₂ alkyls. Non-limitingexamples of C₁-C₁₂ alkyl include methyl, ethyl, n-propyl, i-propyl,sec-propyl, n-butyl, 1-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl,n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl.Unless stated otherwise, an alkyl group can be unsubstituted orsubstituted with a substituent disclosed herein.

“Alkylene” refers to a fully saturated, straight or branched divalenthydrocarbon, and having from one to twelve carbon atoms. Non-limitingexamples of C₁-C₁₂ alkylene include methylene, ethylene, propylene,n-butylene, and the like. Each alkylene terminus is attached to an atomby a single bond. The points of attachment of the alkylene chain can beone or two atoms. Unless stated otherwise, an alkylene chain can beunsubstituted or substituted with a substituent disclosed herein.

“Alkenyl” refers to a straight or branched hydrocarbon chain having fromtwo to twelve carbon atoms, and having one or more carbon-carbon doublebonds. Each alkenyl group is attached to an atom by a single bond.Alkenyl groups with a number of carbon atoms ranging from 2 to 12 areincluded. An alkenyl group with 2 to 12 carbon atoms is a C₂-C₁₂alkenyl, an alkenyl group with 2 to 10 carbon atoms is a C₂-C₁₀ alkenyl,an alkenyl group with 2 to 6 carbon atoms is a C₂-C₆ alkenyl and analkenyl group with 2 to 5 carbon atoms is a C₂-C₅ alkenyl. A C₂-C₅alkenyl includes C₅ alkenyls, C₄ alkenyls, C₃ alkenyls, and C₂ alkenyls.A C₂-C₆ alkenyl includes all moieties described above for C₂-C₅ alkenylsbut also includes C₆ alkenyls. A C₂-C₁₀ alkenyl includes all moietiesdescribed above for C₂-C₅ alkenyls and C₂-C₆ alkenyls, but also includesC₇, C₈, C₉ and C₁₀ alkenyls. Similarly, a C₂-C₁₂ alkenyl includes allthe foregoing moieties, but also includes Cn and C₁₂ alkenyls.Non-limiting examples of C₂-C₁₂ alkenyl include ethenyl (vinyl),1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl,1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl,1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl,7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl,6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl,4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl,1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl,6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl,1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl,6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and11-dodecenyl. Unless stated otherwise, an alkyl group can beunsubstituted or substituted with a substituent disclosed herein.

“Alkenylene” refers to a straight or branched divalent hydrocarbon chainradical, having from two to twelve carbon atoms, and having one or morecarbon-carbon double bonds. Non-limiting examples of C₂-C₁₂ alkenyleneinclude ethenylene, propenylene, butenylene, and the like. Each terminusof the alkenylene chain is attached to an atom by a single bond. Thepoints of attachment of the alkenylene chain can be through one twoatoms. Unless stated otherwise, an alkenylene chain can be unsubstitutedor substituted with a substituent disclosed herein.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalhaving from two to twelve carbon atoms, and having one or morecarbon-carbon triple bonds. Each alkynyl group is attached to an atom bya single bond. Alkynyl groups with a number of carbon atoms ranging from2 to 12 are included. An alkynyl group having 2 to 12 carbon atoms is aC₂-C₁₂ alkynyl, an alkynyl group with 2 to 10 carbon atoms is a C₂-C₁₀alkynyl, an alkynyl group with 2 to 6 carbon atoms is a C₂-C₆ alkynyland an alkynyl group with 2 to 5 carbon atoms is a C₂-C₅ alkynyl. AC₂-C₅ alkynyl includes C₅ alkynyls, C₄ alkynyls, C₃ alkynyls, and C₂alkynyls. A C₂-C₆ alkynyl includes all moieties described above forC₂-C₅ alkynyls but also includes C₆ alkynyls. A C₂-C₁₀ alkynyl includesall moieties described above for C₂-C₅ alkynyls and C₂-C₆ alkynyls, butalso includes C₇, C₈, C₉ and C₁₀ alkynyls. Similarly, a C₂-C₁₂ alkynylincludes all the foregoing moieties, but also includes Cn and C₁₂alkynyls. Non-limiting examples of C₂-C₁₂ alkenyl include ethynyl,propynyl, butynyl, pentynyl and the like. Unless stated otherwise, analkyl group can be unsubstituted or substituted with a substituentdisclosed herein.

“Alkynylene” refers to a straight or branched divalent hydrocarbon chainradical, having from two to twelve carbon atoms, and having one or morecarbon-carbon triple bonds. Non-limiting examples of C₂-C₁₂ alkynyleneinclude ethynylene, propynylene, butynylene, and the like. Each terminusof the alkynylene chain is attached to an atom through a single bond.The points of attachment of the alkynylene chain can be through one ortwo atoms. Unless stated otherwise, an alkynylene chain can beunsubstituted or substituted with a substituent disclosed herein.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl, alkenyl or alknyl radical as defined herein. Unless statedotherwise, an alkoxy group can be unsubstituted or substituted with asubstituent disclosed herein.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 18 carbon atoms and at least one aromatic ring. The aryl radicalcan be a monocyclic, bicyclic, tricyclic or tetracyclic ring system,which can include fused or bridged ring systems. Aryl radicals include,but are not limited to, aceanthrylenyl, acenaphthylenyl,acephenanthrylenyl, anthracenyl, azulenyl, chrysenyl, fluoranthenyl,fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, naphthalenyl,phenalenyl, phenanthrenyl, phenyl, pleiadenyl, pyrenyl, andtriphenylenyl. Unless stated otherwise, the aryl can be unsubstituted orsubstituted with a substituent disclosed herein.

“Arylene” refers to a divalent aryl group, wherein the aryl is asdefined herein. Unless stated otherwise, an arylene group can beunsubstituted or substituted with a substituent disclosed herein.

“Arylalkyl” refers to a radical of the formula —R_(b)—R_(c) where R_(b)is an alkylene group as defined herein and R_(c) is an aryl radical asdefined herein, for example, benzyl, diphenylmethyl and the like. Unlessstated otherwise, an arylalkyl group can be unsubstituted or substitutedwith a substituent disclosed herein. “Arylalkenyl” refers to a radicalof the formula —R_(b)—R_(c) where R_(b) is an alkenylene group asdefined herein and R_(c) is an aryl radical as defined herein. Unlessstated otherwise, an arylalkenyl group can be unsubstituted orsubstituted with a substituent disclosed herein.

“Arylalkynyl” refers to a radical of the formula —R_(b)—R_(c) whereR_(b) is an alkynylene group as defined herein and R_(c) is an arylradical as defined herein. Unless stated otherwise, an arylalkynyl groupcan be unsubstituted or substituted with a substituent disclosed herein.

“Cycloalkyl” refers to a non-aromatic monocyclic or polycyclic fullysaturated hydrocarbon radical consisting of carbon and hydrogen atoms,which can include fused or bridged ring systems, having from three totwenty carbon atoms, preferably having from three to ten carbon atoms,and which is attached to an atom by a single bond. Monocyclic cycloalkylradicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicalsinclude, for example, adamantyl, norbornyl, decalinyl,7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless statedotherwise, a cycloalkyl group can be unsubstituted or substituted with asubstituent disclosed herein.

“Aryloxy” refers to a radical of the formula —O(aryl), wherein the arylradical is as defined herein. Aryloxy includes, but are is not limitedto, phenoxy (—O(phenyl)). Unless stated otherwise, an aryloxy group canbe unsubstituted or substituted with a substituent disclosed herein.

“Cycloalkenyl” refers to a non-aromatic monocyclic or polycyclichydrocarbon radical consisting of carbon and hydrogen atoms and havingone or more carbon-carbon double bonds. Cycloalkenyl can include fusedor bridged ring systems, having from three to twenty carbon atoms, insome embodiments having from three to ten carbon atoms. A cycloalkenylgroup is attached to an atom by a single bond. Monocyclic cycloalkenylradicals include, for example, cyclopentenyl, cyclohexenyl,cycloheptenyl, cycloctenyl, and the like. Polycyclic cycloalkenylradicals include, for example, bicyclo[2.2.1]hept-2-enyl and the like.Unless stated otherwise, a cycloalkenyl group can be unsubstituted orsubstituted with a substituent disclosed herein.

“Cycloalkynyl” refers to a non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,having one or more carbon-carbon triple bonds, which can include fusedor bridged ring systems, having from five to twenty carbon atoms, insome embodiments having from five to ten carbon atoms, and which isattached to the rest of the molecule by a single bond. Monocycliccycloalkynyl radicals include, for example, cycloheptynyl, cyclooctynyl,and the like. Unless stated otherwise, a cycloalkynyl group can beunsubstituted or substituted with a substituent disclosed herein.

“Cycloalkylalkyl” refers to a radical of the formula —R_(b)—R_(d) whereR_(b) is an alkylene group as defined herein and R_(d) is a cycloalkylradical as defined herein. Unless stated otherwise, a cycloalkylalkylgroup can be unsubstituted or substituted with a substituent disclosedherein. “Cycloalkylalkenyl” refers to a radical of the formula—R_(b)—R_(d) where R_(b) is an alkenylene group as defined herein andR_(d) is a cycloalkyl radical as defined herein. Unless statedotherwise, a cycloalkylalkenyl group can be unsubstituted or substitutedwith a substituent disclosed herein. “Cycloalkylalkynyl” refers to aradical of the formula —R_(b)—R_(d) where R_(b) is an alkynylene groupas defined herein and R_(d) is a cycloalkyl radical as defined herein.Unless stated otherwise, a cycloalkylalkynyl group can be unsubstitutedor substituted with a substituent disclosed herein.

“Cycloalkenylalkyl” refers to a radical of the formula —R_(b)—R_(d)where R_(b) is an alkylene group as defined herein and R_(d) is acycloalkenyl radical as defined herein. Unless stated otherwise, acycloalkenylalkyl group can be unsubstituted or substituted with asubstituent disclosed herein. “Cycloalkenylalkenyl” refers to a radicalof the formula —R_(b)—R_(d) where R_(b) is an alkenylene group asdefined herein and R_(d) is a cycloalkyl radical as defined herein.Unless stated otherwise, a cycloalkenylalkenyl group can beunsubstituted or substituted with a substituent disclosed herein.“Cycloalkenylalkynyl” refers to a radical of the formula —R_(b)—R_(d)where R_(b) is an alkynylene group as defined herein and R_(d) is acycloalkyl radical as defined herein. Unless stated otherwise, acycloalkenylalkynyl group can be unsubstituted or substituted with asubstituent disclosed herein.

“Cycloalkynylalkyl” refers to a radical of the formula —R_(b)—R_(d)where R_(b) is an alkylene group as defined herein and R_(d) is acycloalkynyl radical as defined herein. Unless stated otherwise, acycloalkynylalkyl group can be unsubstituted or substituted with asubstituent disclosed herein. “Cycloalkynylalkenyl” refers to a radicalof the formula —R_(b)—R_(d) where R_(b) is an alkenylene group asdefined herein and R_(d) is a cycloalkyl radical as defined herein.Unless stated otherwise, a cycloalkynylalkenyl group can beunsubstituted or substituted with a substituent disclosed herein.“Cycloalkynylalkynyl” refers to a radical of the formula —R_(b)—R_(d)where R_(b) is an alkynylene group as defined herein and R_(d) is acycloalkyl radical as defined herein. Unless stated otherwise, acycloalkynylalkynyl group can be unsubstituted or substituted with asubstituent disclosed herein.

“Carbocyclyl,” “carbocyclic ring” or “carbocycle” refers to a ringstructure, wherein the atoms which form the ring are each carbon. Thecarbocyclyl, carbocyclic ring or carbocycle can comprise from 3 to 20carbon atoms in the ring. The carbocyclyl, carbocyclic ring orcarbocycle includes aryl, cycloalkyl, cycloalkenyl and cycloalkynyl asdefined herein. The carbocyclyl, carbocyclic ring or carbocycle can be amonocyclic, bicyclic, tricyclic or tetracyclic ring system, which caninclude fused, bridged, and spiral ring systems. Unless statedotherwise, a carbocyclyl group, carbocyclic ring or carbocycle can beunsubstituted or substituted with a substituent disclosed herein.

“Haloalkyl” refers to an alkyl radical, as defined herein, that issubstituted by one or more halo radicals, as defined herein, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and thelike. Unless stated otherwise, a haloalkyl group can be unsubstituted orsubstituted with a substituent disclosed herein.

“Haloalkenyl” refers to an alkenyl radical, as defined herein, that issubstituted by one or more halo radicals, as defined herein, e.g.,1-fluoropropenyl, 1,1-difluorobutenyl, and the like. Unless statedotherwise, a haloalkenyl group can be unsubstituted or substituted witha substituent disclosed herein.

“Haloalkynyl” refers to an alkynyl radical, as defined herein, that issubstituted by one or more halo radicals, as defined herein, e.g.,1-fluoropropynyl, 1-fluorobutynyl, and the like. Unless statedotherwise, a haloalkenyl group can be unsubstituted or substituted witha substituent disclosed herein.

“Heterocyclyl” refers to a 3- to 20-membered non-aromatic, partiallyunsaturated, or aromatic ring radical which includes two to twelvecarbon atoms and from one to six nitrogen, oxygen or sulfur heteroatoms.Heterocyclyl include heteroaryls as defined herein. Unless statedotherwise, the heterocyclyl radical can be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which can include fused, bridged,and spiral ring systems; and the nitrogen, carbon or sulfur atoms in theheterocyclyl radical can be optionally oxidized; the nitrogen atom canbe optionally quaternized; and the heterocyclyl radical can be partiallyor fully saturated. Examples of heterocyclyl radicals include, but arenot limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl,imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise, a heterocyclyl groupcan be unsubstituted or substituted with a substituent disclosed herein.

“Heterocyclylalkyl” refers to a radical of the formula —R_(b)—R_(e)where R_(b) is an alkylene group as defined herein and R_(e) is aheterocyclyl radical as defined herein. Unless stated otherwise, aheterocyclylalkyl group can be unsubstituted or substituted with asubstituent disclosed herein.

“Heterocyclylalkenyl” refers to a radical of the formula —R_(b)—R_(e)where R_(b) is an alkenylene group as defined herein and R_(e) is aheterocyclyl radical as defined herein. Unless stated otherwise, aheterocyclylalkenyl group can be unsubstituted or substituted with asubstituent disclosed herein.

“Heterocyclylalkynyl” refers to a radical of the formula —R_(b)—R_(e)where R_(b) is an alkynylene group as defined herein and R_(e) is aheterocyclyl radical as defined herein. Unless stated otherwise, aheterocyclylalkynyl group can be unsubstituted or substituted with asubstituent disclosed herein.

“N-heterocyclyl” refers to a heterocyclyl radical as defined hereinincluding at least one nitrogen and where the point of attachment of theheterocyclyl radical of an atom of a compound of the invention isthrough a nitrogen atom in the heterocyclyl radical. Unless statedotherwise, an N-heterocyclyl group can be unsubstituted or substitutedwith a substituent disclosed herein.

“Heteroaryl” refers to a 5- to 20-membered ring system radical includinghydrogen atoms, one to thirteen carbon atoms, one to six nitrogen,oxygen or sulfur heteroatoms, and at least one aromatic ring. Theheteroaryl radical can be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which can include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical can be optionally oxidized; the nitrogen atom can be optionallyquaternized. Examples of heteroaryl include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl,benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl,benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophene), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophene, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thienyl). Unless stated otherwise, a heteroaryl group canbe unsubstituted or substituted.

“N-heteroaryl” refers to a heteroaryl radical as defined herein havingat least one nitrogen atom and where the point of attachment of theheteroaryl radical to an atom of the compound of the invention isthrough a nitrogen atom in the heteroaryl radical. Unless statedotherwise, an N-heteroaryl group can be unsubstituted or substitutedwith a substituent disclosed herein.

“Heteroarylalkyl” refers to a radical of the formula —R_(b)—R_(f) whereR_(b) is an alkylene chain as defined herein and R_(f) is a heteroarylradical as defined herein. Unless stated otherwise, a heteroaryl alkylgroup can be unsubstituted or substituted with a substituent disclosedherein.

“Heteroarylalkenyl” refers to a radical of the formula —R_(b)—R_(f)where R_(b) is an alkenylene chain as defined herein and R_(f) is aheteroaryl radical as defined herein. Unless stated otherwise, aheteroarylalkenyl group can be unsubstituted or substituted with asubstituent disclosed herein.

“Heteroarylalkynyl” refers to a radical of the formula —R_(b)—R_(f)where R_(b) is an alkynylene chain as defined herein and R_(f) is aheteroaryl radical as defined herein. Unless stated otherwise, aheteroarylalkynyl group can be unsubstituted or substituted with asubstituent disclosed herein.

“Ring” refers to a cyclic group which can be saturated or include one ormore double or triple bonds. A ring can be monocyclic, bicyclic,tricyclic, or tetracyclic. Unless stated otherwise, a ring can beunsubstituted or substituted with a substituent disclosed herein.

“Thioalkyl” refers to a radical of the formula —SR_(a) where R_(a) is analkyl, alkenyl, or alkynyl radical as defined herein. Unless statedotherwise, a thioalkyl group can be unsubstituted or substituted with asubstituent disclosed herein.

A group or radical disclosed herein can be substituted with one or moreof the following substitutents: a halogen atom such as F, Cl, Br, and I;a hydroxyl, alkoxy, or ester; thiol, thioalkyl, sulfone, sulfonyl, orsulfoxide; amine, amide, alkylamine, dialkylamine, arylamine,alkylarylamine, diarylamine, N-oxide, imide, and enamine; trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl; and other groups,optionally including one or more heteroatoms.

A group or radical disclosed herein can be alternatively or additionallysubstituted with one or more of the following substituents: oxo,carbonyl, carboxyl, or an ester group; or an imine, oxime, hydrazone,and nitrile.

Examples of other substituents include, but are not limited to:

an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl,alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, arylalkyl,cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl,haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl,heterocyclylalkyl, heteroaryl, N-heteroaryl and heteroaryl alkyl group,—NR_(g)R_(h), —NR_(g)C(═O)R_(h), —NR_(g)C(═O)NR_(g)R_(h),—NR_(g)C(═O)OR_(h), —NR_(g)SO₂R_(h), —OC(═O)NR_(g)R_(h), —OR_(g),—SR_(g), —SOR_(g), —SO₂R_(g), —OSO₂R_(g), —SO₂OR_(g), ═NSO₂R_(g),—SO₂NR_(g)R_(h), —C(═O)R_(g), —C(═O)OR_(g), —C(═O)NR_(g)R_(h),—CH₂SO₂R_(g) and —CH₂SO₂NR_(g)R_(h), wherein R_(g) and R_(h) are thesame or different and independently hydrogen, alkyl, alkenyl, alkynyl,alkoxy, alkylamino, thioalkyl, aryl, arylalkyl, cycloalkyl,cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl,haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl,heteroaryl, N-heteroaryl or heteroarylalkyl, wherein each of theforegoing substituents is unsubstituted or substituted with one or moresubstituents disclosed herein.

As used herein, the symbol

(a “point of attachment bond”) denotes a bond that is a point ofattachment between two chemical entities, one of which is depicted asbeing attached to the point of attachment bond and the other of which isnot depicted as being attached to the point of attachment bond. Forexample,

indicates that the chemical entity “XY” is bonded to another chemicalentity via the point of attachment bond.

The Compounds of the Invention

Compounds of Formula (IA)

In some embodiments, the compound of the invention is a compound ofFormula (IA):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

-   -   each p is independently 1, 2, 3, 4, 5, 6, or 7;    -   Z¹ and Z² are independently —C(R^(1A))(R^(2A))—(CH₂)_(d)—X^(A)        or —W—(CH₂)_(d)—C(R³)(R⁴)—Y;    -   each d is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;    -   each R^(1A) and R^(2A) is independently H, —C₁-C₆ alkyl, —C₂-C₆        alkenyl, —C₂-C₆ alkynyl, phenyl or benzyl, or each carbon atom        together with the R^(1A) and R^(2A) attached to the carbon atom        independently form a —C₃-C₇ cycloalkyl group;    -   each R³ and R⁴ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, —O(C₁-C₆ alkyl), phenyl, benzyl, Cl, Br, CN,        NO₂, or CF₃, or each carbon atom together with the R³ and R⁴        attached to the carbon atom independently form a —C₃-C₇        cycloalkyl group;    -   each X^(A) is independently H, —OH, —SO₃H,

-   -   each R⁶ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl, wherein the —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl is unsubstituted or substituted with one or two        halogen, —OH, —O(C₁-C₆ alkyl), or phenyl groups;    -   each R⁷ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl;    -   each W is independently —O—, —NH—, —N(OH)—, —N(→O)—, —S—,        —S(═O)—, —S(O)₂—, or —Se—;    -   each Y is independently —OH, —COOH, —COOR⁵, —SO₃H,

each R⁵ is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl,phenyl, or benzyl, each being unsubstituted or substituted with one ormore halogen, —OH, —O(C₁-C₆ alkyl), or phenyl groups.

In some embodiments of the compounds of Formula (IA), Z¹ and Z² areindependently —C(R^(1A))(R^(2A))—(CH₂)_(d)—X^(A).

In some embodiments of the compounds of Formula (IA), each R^(1A) andR^(2A) is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or —C₂-C₆ alkynyl.In some embodiments, each R^(1A) and R^(2A) is independently —C₁-C₃alkyl, —C₂-C₃ alkenyl, or —C₂-C₃ alkynyl. In some embodiments, eachR^(1A) and R^(2A) is independently H or —C₁-C₆ alkyl. In someembodiments, R^(1A) and R^(2A) are methyl.

In some embodiments of the compounds of Formula (IA), each p is 2, 3, 4,or 5.

In some embodiments of the compounds of Formula (IA), each d is 0, 1, 2,or 3. In some embodiments, d is 0 or 1.

In some embodiments, the compound of the invention is a compound ofFormula (IA):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

-   -   each p is independently 4, 5, 6, or 7;    -   Z¹ and Z² are independently —C(R¹)(R²)—(CH₂)_(c)—X or        —W—(CH₂)_(c)—C(R³)(R⁴)—Y;    -   each c is independently 0, 1, 2, or 3;    -   each R¹ and R² is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, phenyl or benzyl, or each carbon atom together        with the R¹ and R² attached to the carbon atom independently        form a —C₃-C₇ cycloalkyl group;    -   each R³ and R⁴ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, —O(C₁-C₆ alkyl), phenyl, benzyl, Cl, Br, CN,        NO₂, or CF₃, or each carbon atom together with the R³ and R⁴        attached to the carbon atom independently form a —C₃-C₇        cycloalkyl group;    -   each X and Y is independently —OH, —COOH, —COOR⁵, —SO₃H,

-   -   each R⁶ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl, wherein the —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl is unsubstituted or substituted with one or two        halogen, —OH, —O(C₁-C₆ alkyl), or phenyl groups;    -   each R⁷ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl;    -   each W is independently —O—, —NH—, —N(OH)—, —N(→O)—, —S—,        —S(═O)—, —S(O)₂—, or —Se—; and    -   each R⁵ is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆        alkynyl, phenyl, or benzyl, each being unsubstituted or        substituted with one or more halogen, —OH, —O(C₁-C₆ alkyl), or        phenyl groups.

In some embodiments, the compound of Formula (IA) has any one of thestructures shown in Table A-1, or a pharmaceutically acceptable salt orsolvate thereof.

TABLE A-1 Compound No. Structure and Name I-1

6-[4-(5-Carboxy-5-methyl-hexyl)-phenyl]-2,2-dimethylhexanoic acid I-2

7-(4-(5-Carboxy-5-methylhexyl)phenyl)-2,2-dimethylheptanoic acid I-3

7,7′-(1,4-Phenylene)bis(2,2-dimethylheptanoic acid) I-4

8-(4-(5-Carboxy-5-methylhexyl)phenyl)-2,2-dimethyloctanoic acid I-5

1-(5-(4-(4-(1-carboxycyclopropyl)butyl)phenyl)pentyl)cyclopropane-1-carboxylic acid I-6

1-(6-(4-(4-(1-carboxycyclopropyl)butyl)phenyl)hexyl)cyclopropane-1-carboxylic acid I-7

1,1′-(1,4-phenylenebis(pentane-5,1-diyl))bis(cyclopropane-1-carboxylicacid) I-8

1-(4-(4-(6-carboxy-6-methylheptyl)phenyl)butyl)cyclopropane-1-carboxylic acid I-9

1-(4-(4-(7-carboxy-7-methyloctyl)phenyl)butyl)cyclopropane-1- carboxylicacid I-10

1-(5-(4-(6-carboxy-6-methylheptyl)phenyl)pentyl)cyclopropane-1-carboxylic acid

Compounds of Formula (IB)

In some embodiments, the compound of the invention is a compound ofFormula (IB):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

-   -   each p is independently 1, 2, 3, 4, 5, 6, or 7;    -   each Z¹ and Z² is independently —C(R¹)(R²)—(CH₂)_(c)—X or        —W—(CH₂)_(c)—C(R³)(R⁴)—Y;    -   each c is independently 0, 1, 2, or 3;    -   each R¹ and R² is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, phenyl or benzyl, or each carbon atom together        with the R¹ and R² attached to the carbon atom independently        form a —C₃-C₇ cycloalkyl group;    -   each R³ and R⁴ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, —O(C₁-C₆ alkyl), phenyl, benzyl, Cl, Br, CN,        NO₂, or CF₃, or each carbon atom together with the R³ and R⁴        attached to the carbon atom independently form a —C₃-C₇        cycloalkyl group;    -   each X and Y is independently —OH, —COOH, —COOR⁵, —SO₃H,

-   -   each R⁶ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl, wherein the —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl is unsubstituted or substituted with one or two        halogen, —OH, —O(C₁-C₆ alkyl), or phenyl groups;    -   each R⁷ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl;    -   each W is independently —O—, —NH—, —N(OH)—, —N(→O)—, —S—,        —S(═O)—, —S(O)₂—, or —Se—; and    -   each R⁵ is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆        alkynyl, phenyl, or benzyl, each being unsubstituted or        substituted with one or more halogen, —OH, —O(C₁-C₆ alkyl), or        phenyl groups.

In some embodiments, the compound of Formula (IB) has any one of thestructures shown in Table A-2, or a pharmaceutically acceptable salt orsolvate thereof.

TABLE A-2 Compound No. Structure and Name I-31

5-[3-(4-Carboxy-4-methylpentyl)phenyl]-2,2-dimethylpenatnoic acid I-32

6-[3-(5-Carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoic acid I-33

7-(3-(5-Carboxy-5-methylhexyl)phenyl)-2,2-dimethylheptanoic acid I-34

7,7′-(1,3-Phenylene)bis(2,2-dimethylheptanoic acid) I-35

8-(3-(5-Carboxy-5-methylhexyl)phenyl)-2,2-dimethyloctanoic acid I-36

8,8′-(1,3-Phenylene)bis(2,2-dimethyloctanoic acid) I-37

1-(6-(3-(7-carboxy-7-methyloctyl)phenyl)hexyl)cyclopropane-1- carboxylicacid I-38

1,1′-(1,3-phenylenebis(hexane-6,1-diyl))bis(cyclopropane-1-carboxylicacid) I-39

1-(4-(3-(6-carboxy-6-methylheptyl)phenyl)butyl)cyclopropane-1-carboxylic acid I-40

1-(5-(3-(6-carboxy-6-methylheptyl)phenyl)pentyl)cyclopropane-1-carboxylic acid I-41

1-(4-(3-(7-carboxy-7-methyloctyl)phenyl)butyl)cyclopropane-1- carboxylicacid I-42

1-(5-(3-(4-(1-carboxycyclopropyl)butyl)phenyl)pentyl)cyclopropane-1-carboxylic acid I-43

1,1′-(1,3-phenylenebis(pentane-5,1-diyl))bis(cyclopropane-1-carboxylicacid) I-44

1-(6-(3-(4-(1-carboxycyclopropyl)butyl)phenyl)hexyl)cyclopropane-1-carboxylic acid

Compounds of Formula (IC)

In some embodiments, the compound of the invention is a compound ofFormula (IC):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

-   -   each p is independently 1, 2, 3, 4, 5, 6, or 7;    -   each Z¹ and Z² is independently —C(R¹)(R²)—(CH₂)_(c)—X or        —W—(CH₂)_(c)—C(R³)(R⁴)—Y;    -   each c is independently 0, 1, 2, or 3;    -   each R¹ and R² is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, phenyl or benzyl, or each carbon atom together        with the R¹ and R² attached to the carbon atom independently        form a —C₃-C₇ cycloalkyl group;    -   each R³ and R⁴ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, —O(C₁-C₆ alkyl), phenyl, benzyl, Cl, Br, CN,        NO₂, or CF₃, or each carbon atom together with the R³ and R⁴        attached to the carbon atom independently form a —C₃-C₇        cycloalkyl group;    -   each X and Y is independently —OH, —COOH, —COOR⁵, —SO₃H,

-   -   each R⁶ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl, wherein the —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl is unsubstituted or substituted with one or two        halogen, —OH, —O(C₁-C₆ alkyl), or phenyl groups;    -   each R⁷ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl;    -   each W is independently —O—, —NH—, —N(OH)—, —N(→O)—, —S—,        —S(═O)—, —S(O)₂—, or —Se—; and    -   each R⁵ is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆        alkynyl, phenyl, or benzyl, each being unsubstituted or        substituted with one or more halogen, —OH, —O(C₁-C₆ alkyl), or        phenyl groups.

In some embodiments of the compounds of Formula (IA), (IB), or (IC), Z¹and Z² are each independently —C(R¹)(R²)—(CH₂)_(c)—X. In someembodiments, one or both of Z¹ and Z² is —W—(CH₂)_(C)—C(R³)(R⁴)—Y.

In some embodiments of the compounds of Formula (IA), (IB), or (IC), Xis —COOH or —COOR⁵.

In some embodiments of the compounds of Formula (IA), (IB), or (IC),each R¹ and R² is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or —C₂-C₆alkynyl. In some embodiments, each R¹ and R² is independently —C₁-C₃alkyl, —C₂-C₃ alkenyl, or —C₂-C₃ alkynyl. In some embodiments, R¹ and R²are methyl.

In some embodiments of the compounds of Formula (IA), (IB), or (IC), Z¹and Z² are each independently —C(R¹)(R²)—(CH₂)_(c)—X, X is —COOH or—COOR⁵, and R¹ and R² are methyl.

In some embodiments of the compounds of Formula (IA), (IB), or (IC), cis 0 or 1.

In some embodiments of the compounds of Formula (IA), (IB), or (IC), Z¹and Z² are each —C(R¹)(R²)—(CH₂)_(C)—X. In some embodiments, Z¹ and Z²are each —C(R¹)(R²)—(CH₂)_(c)—X and X is each —COOH.

In some embodiments of the compounds of Formula (IA), (IB), or (IC),each carbon atom together with the R¹ and R² attached to the carbon atomindependently form a —C₃-C₇ cycloalkyl group. In some embodiments, eachcarbon atom together with the R¹ and R² attached to the carbon atomindependently form a cyclopropyl ring.

In some embodiments of the compounds of Formula (IA), (IB), or (IC), Z¹and Z² are each —C(R¹)(R²)—(CH₂)_(c)—X and at least one R¹ and one R²together with the carbon atom to which they are attached form a —C₃-C₇cycloalkyl group. In some embodiments, Z¹ and Z² are each—C(R¹)(R²)—(CH₂)_(c)—X and at least one R¹ and one R² together with thecarbon atom to which they are attached form a cyclopropyl ring.

In some embodiments of the compounds of Formula (IA), (IB), or (IC), R³and R⁴ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or —C₂-C₆alkynyl.

In some embodiments of the compounds of Formula (IA), (IB), or (IC), Yis —COOH or —COOR⁵.

In some embodiments of the compounds of Formula (IA), (IB), or (IC), R⁵is —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or —C₂-C₆ alkynyl. In some embodiments,R⁵ is —C₁-C₃ alkyl, —C₂-C₃ alkenyl, or —C₂-C₃ alkynyl.

In some embodiments of the compounds of Formula (IA), (IB), or (IC), pis 3, 4, 5, 6, or 7. In some embodiments, p is 4, 5, 6, or 7.

In some embodiments of the compounds of Formula (IA), (IB), or (IC), oneor both of Z¹ and Z² is —W—(CH₂)_(C)—C(R³)(R⁴)—Y, and R³ and R⁴ isindependently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or —C₂-C₆ alkynyl. Insome embodiments, one or both of Z¹ and Z² is —W—(CH₂)_(c)—C(R³)(R⁴)—Y,and Y is —COOH or —COOR⁵. In some embodiments, one or both of Z¹ and Z²is —W—(CH₂)_(C)—C(R³)(R⁴)—Y, Y is —COOH or —COOR⁵, and R⁵ is —C₁-C₆alkyl, —C₂-C₆ alkenyl, or —C₂-C₆ alkynyl. In some embodiments, one orboth of Z¹ and Z² is —W—(CH₂)_(c)—C(R³)(R⁴)—Y, Y is —COOH or —COOR⁵, andR⁵ is —C₁-C₃ alkyl, —C₂-C₃ alkenyl, or —C₂-C₃ alkynyl.

In some embodiments, the compound of Formula (IC) has of any one of thestructures shown in Table A-3, or a pharmaceutically acceptable salt orsolvate thereof.

TABLE A-3 Compound No. Structure and Name I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

Compounds of Formula (ID)

In some embodiments, the compound of the invention is a compound ofFormula (ID):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

-   -   each p is independently 1, 2, 3, 4, 5, 6, or 7;    -   Z¹ and Z² are independently —C(R^(1A))(R^(2A))—(CH₂)_(d)—X^(A)        or —W—(CH₂)_(d)—C(R³)(R⁴)—Y;    -   each d is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;    -   each R^(1A) and R^(2A) is independently H, —C₁-C₆ alkyl, —C₂-C₆        alkenyl, —C₂-C₆ alkynyl, phenyl or benzyl, or each carbon atom        together with the R^(1A) and R^(2A) attached to the carbon atom        independently form a —C₃-C₇ cycloalkyl group;    -   each R³ and R⁴ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, —O(C₁-C₆ alkyl), phenyl, benzyl, Cl, Br, CN,        NO₂, or CF₃, or each carbon atom together with the R³ and R⁴        attached to the carbon atom independently form a —C₃-C₇        cycloalkyl group;

Q¹ and Q² are independently H, OH, —C₁-C₆ alkyl, —O(C₁-C₆ alkyl),phenoxy, aryloxy, benzyl, —S-aryl, —SR^(1A), —NR^(1A)R^(2A), F, Cl, Br,I, —CF₃, —COR^(1A), heteroaryl, heterocyclyl, or —V—OH, or each carbonatom together with the Q¹ and Q² attached to the carbon atomindependently form a heterocyclyl or a carbocyclyl group;

-   -   V is (CH₂)_(t) or arylene;    -   t is 0, 1, 2, 3, or 4;    -   each X^(A) is independently H, —OH, —SO₃H,

-   -   each R⁶ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl, wherein the —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl is unsubstituted or substituted with one or two        halogen, —OH, —O(C₁-C₆ alkyl), or phenyl groups;    -   each R⁷ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl;    -   each W is independently —O—, —NH—, —N(OH)—, —N(→O)—, —S—,        —S(═O)—, —S(O)₂—, or —Se—;    -   each Y is independently —OH, —COOH, —COOR⁵, —SO₃H,

-   -   each R⁵ is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆        alkynyl, phenyl, or benzyl, each being unsubstituted or        substituted with one or more halogen, —OH, —O(C₁-C₆ alkyl), or        phenyl groups.

In some embodiments of the compounds of Formula (ID), Z¹ and Z² areindependently —C(R^(1A))(R^(2A))—(CH₂)_(d)—X^(A).

In some embodiments of the compounds of Formula (ID), each R^(1A) andR^(2A) is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or —C₂-C₆ alkynyl.In some embodiments, each R^(1A) and R^(2A) is independently —C₁-C₃alkyl, —C₂-C₃ alkenyl, or —C₂-C₃ alkynyl. In some embodiments, eachR^(1A) and R^(2A) is independently H or —C₁-C₆ alkyl. In someembodiments, R^(1A) and R^(2A) are methyl.

In some embodiments of the compounds of Formula (ID), each p is 2, 3, 4,or 5.

In some embodiments of the compounds of Formula (ID), each d is 0, 1, 2,or 3. In some embodiments, d is 0 or 1.

In some embodiments, the compound of the invention is a compound ofFormula (ID):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

-   -   each p is independently 4, 5, 6, or 7;    -   Z¹ and Z² are independently —C(R¹)(R²)—(CH₂)_(c)—X or        —W—(CH₂)_(c)—C(R³)(R⁴)—Y;    -   each c is independently 0, 1, 2, or 3;    -   each R¹ and R² is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, phenyl or benzyl, or each carbon atom together        with the R¹ and R² attached to the carbon atom independently        form a —C₃-C₇ cycloalkyl group;    -   each R³ and R⁴ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, —O(C₁-C₆ alkyl), phenyl, benzyl, Cl, Br, CN,        NO₂, or CF₃, or each carbon atom together with the R³ and R⁴        attached to the carbon atom independently form a —C₃-C₇        cycloalkyl group;    -   Q¹ and Q² are independently H, OH, —C₁-C₆ alkyl, —O(C₁-C₆        alkyl), phenoxy, aryloxy, benzyl, —S-aryl, —SR^(1A),        —NR^(1A)R^(2A), F, Cl, Br, I, —CF₃, —COR^(1A), heteroaryl,        heterocyclyl, or —V—OH, or each carbon atom together with the Q¹        and Q² attached to the carbon atom independently form a        heterocyclyl or a carbocyclyl group;    -   each R^(1A) and R^(2A) is independently H, —C₁-C₆ alkyl, —C₂-C₆        alkenyl, —C₂-C₆ alkynyl, phenyl or benzyl;    -   V is (CH₂)_(t) or arylene;    -   t is 0, 1, 2, 3, or 4;    -   each X and Y is independently —OH, —COOH, —COOR⁵, —SO₃H,

-   -   each R⁶ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl, wherein the —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl is unsubstituted or substituted with one or two        halogen, —OH, —O(C₁-C₆ alkyl), or phenyl groups;    -   each R⁷ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl;    -   each W is independently —O—, —NH—, —N(OH)—, —N(→O)—, —S—,        —S(═O)—, —S(O)₂—, or —Se—; and    -   each R⁵ is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆        alkynyl, phenyl, or benzyl, each being unsubstituted or        substituted with one or more halogen, —OH, —O(C₁-C₆ alkyl), or        phenyl groups.

In some embodiments, the compound of Formula (ID) has the structureshown in Table A-1, or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the compound of Formula (ID) has thestructure shown in Table A-5 which are mono- or di-substituted with —OHor methyl groups on the phenyl, or a pharmaceutically acceptable salt orsolvate thereof.

Compounds of Formula (IG)

In some embodiments, the compound of the invention is a compound ofFormula (IG):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

-   -   each p is independently 1, 2, 3, 4, 5, 6, or 7;    -   Z¹ and Z² are independently —C(R¹)(R²)—(CH₂)_(c)—X or        —W—(CH₂)_(c)—C(R³)(R⁴)—Y;    -   each c is independently 0, 1, 2, or 3;    -   each R¹ and R² is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, phenyl or benzyl, or each carbon atom together        with the R¹ and R² attached to the carbon atom independently        form a —C₃-C₇ cycloalkyl group;    -   each R³ and R⁴ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, —O(C₁-C₆ alkyl), phenyl, benzyl, Cl, Br, CN,        NO₂, or CF₃, or each carbon atom together with the R³ and R⁴        attached to the carbon atom independently form a —C₃-C₇        cycloalkyl group;    -   Q¹ and Q² are independently H, OH, —C₁-C₆ alkyl, —O(C₁-C₆        alkyl), phenoxy, aryloxy, benzyl, —S-aryl, —SR^(1A),        —NR^(1A)R^(2A), F, Cl, Br, I, —CF₃, —COR^(1A), heteroaryl,        heterocyclyl, or —V—OH, or each carbon atom together with the Q¹        and Q² attached to the carbon atom independently form a        heterocyclyl or a carbocyclyl group;    -   each R^(1A) and R^(2A) is independently H, —C₁-C₆ alkyl, —C₂-C₆        alkenyl, —C₂-C₆ alkynyl, phenyl or benzyl;    -   V is (CH₂)_(t) or arylene;    -   t is 0, 1, 2, 3, or 4;    -   each X and Y is independently —OH, —COOH, —COOR⁵, —SO₃H,

-   -   each R⁶ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl, wherein the —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl is unsubstituted or substituted with one or two        halogen, —OH, —O(C₁-C₆ alkyl), or phenyl groups;    -   each R⁷ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl;    -   each W is independently —O—, —NH—, —N(OH)—, —N(→O)—, —S—,        —S(═O)—, —S(O)₂—, or —Se—; and    -   each R⁵ is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆        alkynyl, phenyl, or benzyl, each being unsubstituted or        substituted with one or more halogen, —OH, —O(C₁-C₆ alkyl), or        phenyl groups.

In some embodiments, the compound of Formula (IG), Q¹ and Q² are each H.

In some embodiments, the compound of Formula (IG), p is 2, 3, 4, 5, 6,or 7. In some embodiments, the compound of Formula (IG), p is 2.

In some embodiments, the compound of Formula (IG) has the structureshown in Table A-4, or a pharmaceutically acceptable salt or solvatethereof.

Table A-4

TABLE A-4 Compound No. Structure and Name 1-78

Compounds of Formula (IE)

In some embodiments, the compound of the invention is a compound ofFormula (IE):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

-   -   each p is independently 1, 2, 3, 4, 5, 6, or 7;    -   each Z¹ and Z² is independently —C(R¹)(R²)—(CH₂)_(c)—X or        —W—(CH₂)_(c)—C(R³)(R⁴)—Y;    -   each c is independently 0, 1, 2, or 3;    -   each R¹ and R² is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, phenyl or benzyl, or each carbon atom together        with the R¹ and R² attached to the carbon atom independently        form a —C₃-C₇ cycloalkyl group;    -   each R³ and R⁴ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, —O(C₁-C₆ alkyl), phenyl, benzyl, Cl, Br, CN,        NO₂, or CF₃, or each carbon atom together with the R³ and R⁴        attached to the carbon atom independently form a —C₃-C₇        cycloalkyl group;    -   Q¹ and Q² are independently H, OH, —C₁-C₆ alkyl, —O(C₁-C₆        alkyl), phenoxy, aryloxy, benzyl, —S-aryl, —SR^(1A),        —NR^(1A)R^(2A), F, Cl, Br, I, —CF₃, —COR^(1A), heteroaryl,        heterocyclyl, or —V—OH, or each carbon atom together with the Q¹        and Q² attached to the carbon atom independently form a        heterocyclyl or a carbocyclyl group;    -   each R^(1A) and R^(2A) is independently H, —C₁-C₆ alkyl, —C₂-C₆        alkenyl, —C₂-C₆ alkynyl, phenyl or benzyl;    -   V is (CH₂)_(t) or arylene;    -   t is 0, 1, 2, 3, or 4;    -   each X and Y is independently —OH, —COOH, —COOR⁵, —SO₃H,

-   -   each R⁶ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl, wherein the —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl is unsubstituted or substituted with one or two        halogen, —OH, —O(C₁-C₆ alkyl), or phenyl groups;    -   each R⁷ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl;    -   each W is independently —O—, —NH—, —N(OH)—, —N(→O)—, —S—,        —S(═O)—, —S(O)₂—, or —Se—; and    -   each R⁵ is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆        alkynyl, phenyl, or benzyl, each being unsubstituted or        substituted with one or more halogen, —OH, —O(C₁-C₆ alkyl), or        phenyl groups.

In some embodiments, the compound of Formula (IE) has the structureshown in Table A-2, or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the compound of Formula (IE) has thestructure shown in Table A-6 which are mono- or di-substituted with —OHor methyl groups on the phenyl, or a pharmaceutically acceptable salt orsolvate thereof.

Compounds of Formula (IF)

In some embodiments, the compound of the invention is a compound ofFormula (IF):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

-   -   each p is independently 1, 2, 3, 4, 5, 6, or 7;    -   each Z¹ and Z² is independently —C(R¹)(R²)—(CH₂)_(c)—X or        —W—(CH₂)_(c)—C(R³)(R⁴)—Y;    -   each c is independently 0, 1, 2, or 3;    -   each R¹ and R² is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, phenyl or benzyl, or each carbon atom together        with the R¹ and R² attached to the carbon atom independently        form a —C₃-C₇ cycloalkyl group;    -   each R³ and R⁴ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, —O(C₁-C₆ alkyl), phenyl, benzyl, Cl, Br, CN,        NO₂, or CF₃, or each carbon atom together with the R³ and R⁴        attached to the carbon atom independently form a —C₃-C₇        cycloalkyl group;    -   Q¹ and Q² are independently H, OH, —C₁-C₆ alkyl, —O(C₁-C₆        alkyl), phenoxy, aryloxy, benzyl, —S-aryl, —SR^(1A),        —NR^(1A)R^(2A), F, Cl, Br, I, —CF₃, —COR^(1A), heteroaryl,        heterocyclyl, or —V—OH, or each carbon atom together with the Q¹        and Q² attached to the carbon atom independently form a        heterocyclyl or a carbocyclyl group;    -   each R^(1A) and R^(2A) is independently H, —C₁-C₆ alkyl, —C₂-C₆        alkenyl, —C₂-C₆ alkynyl, phenyl or benzyl;    -   V is (CH₂)_(t) or arylene;    -   t is 0, 1, 2, 3, or 4;    -   each X and Y is independently —OH, —COOH, —COOR⁵, —SO₃H,

-   -   each R⁶ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl, wherein the —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl is unsubstituted or substituted with one or two        halogen, —OH, —O(C₁-C₆ alkyl), or phenyl groups;    -   each R⁷ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl;    -   each W is independently —O—, —NH—, —N(OH)—, —N(→O)—, —S—,        —S(═O)—, —S(O)₂—, or —Se—; and    -   each R⁵ is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆        alkynyl, phenyl, or benzyl, each being unsubstituted or        substituted with one or more halogen, —OH, —O(C₁-C₆ alkyl), or        phenyl groups.

In some embodiments, the compound of Formula (IF) has the structureshown in Table A-3, or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the compound of Formula (IE) has thestructure shown in Table A-7 which are mono- or di-substituted with —OHor methyl groups on the phenyl, or a pharmaceutically acceptable salt orsolvate thereof.

Compounds of Formulas (IH) and (IJ)-(IL)

In some embodiments, the compound of the invention is a compound ofFormula (IH):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

-   -   each p is independently 1, 2, 3, 4, 5, 6, or 7;    -   each Z¹ and Z² is independently —C(R¹)(R²)—(CH₂)_(c)—X or        —W—(CH₂)_(c)—C(R³)(R⁴)—Y;    -   each c is independently 0, 1, 2, or 3;    -   each R¹ and R² is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, phenyl or benzyl, or each carbon atom together        with the R¹ and R² attached to the carbon atom independently        form a —C₃-C₇ cycloalkyl group;    -   each R³ and R⁴ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, —O(C₁-C₆ alkyl), phenyl, benzyl, Cl, Br, CN,        NO₂, or CF₃, or each carbon atom together with the R³ and R⁴        attached to the carbon atom independently form a —C₃-C₇        cycloalkyl group;    -   Q is independently —OH, methyl, or methoxy;    -   t is 1, 2, 3, or 4;    -   each X and Y is independently —OH, —COOH, —COOR⁵, —SO₃H,

-   -   each R⁶ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl, wherein the —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl is unsubstituted or substituted with one or two        halogen, —OH, —O(C₁-C₆ alkyl), or phenyl groups;    -   each R⁷ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl;    -   each W is independently —O—, —NH—, —N(OH)—, —N(→O)—, —S—,        —S(═O)—, —S(O)₂—, or —Se—; and    -   each R⁵ is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆        alkynyl, phenyl, or benzyl, each being unsubstituted or        substituted with one or more halogen, —OH, —O(C₁-C₆ alkyl), or        phenyl groups.

In some embodiments of formula (IH), the compound has the structure offormula (IJ), (IK), or (IL), or a pharmaceutically acceptable saltthereof:

In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG),(IH), (IJ), (IK), or (IL) Z¹ and Z² are each independently—C(R¹)(R²)—(CH₂)_(c)—X. In some embodiments of the compounds of Formula(ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), one or both of Z¹ andZ² is —W—(CH₂)_(c)—C(R³)(R⁴)—Y.

In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG),(IH), (IJ), (IK), or (IL), X is —COOH or —COOR⁵.

In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG),(IH), (IJ), (IK), or (IL), each R¹ and R² is independently —C₁-C₆ alkyl,—C₂-C₆ alkenyl, or —C₂-C₆ alkynyl. In some embodiments of the compoundsof Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), each R¹and R² is independently —C₁-C₃ alkyl, —C₂-C₃ alkenyl, or —C₂-C₃ alkynyl.In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG),(IH), (IJ), (IK), or (IL), R¹ and R² are methyl.

In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG),(IH), (IJ), (IK), or (IL), Z¹ and Z² are each independentlyX(R¹)(R²)—(CH₂)_(c)—X, X is —COOH or —COOR⁵, and R¹ and R² are methyl.

In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG),(IH), (IJ), (IK), or (IL), c is 0 or 1.

In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG),(IH), (IJ), (IK), or (IL), Z¹ and Z² are each X(R¹)(R²)—(CH₂)_(c)—X. Insome embodiments of the compounds of Formula (ID), (IE), (IF), (IG),(IH), (IJ), (IK), or (IL), Z¹ and Z² are each —C(R¹)(R²)—(CH₂)_(c)—X andX is each —COOH.

In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG),(IH), (IJ), (IK), or (IL), each carbon atom together with the R¹ and R²attached to the carbon atom independently form a —C₃-C₇ cycloalkylgroup. In some embodiments of the compounds of Formula (ID), (IE), (IF),(IG), (IH), (IJ), (IK), or (IL) each carbon atom together with the R¹and R² attached to the carbon atom independently form a cyclopropylring.

In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG),(IH), (IJ), (IK), or (IL), Z¹ and Z² are each —C(R¹)(R²)—(CH₂)_(c)—X andat least one R¹ and one R² together with the carbon atom to which theyare attached form a —C₃-C₇ cycloalkyl group. In some embodiments of thecompounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL),Z¹ and Z² are each —C(R¹)(R²)—(CH₂)_(c)—X and at least one R¹ and one R²together with the carbon atom to which they are attached form acyclopropyl ring.

In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG),(IH), (IJ), (IK), or (IL), R³ and R⁴ is independently H, —C₁-C₆ alkyl,—C₂-C₆ alkenyl, or —C₂-C₆ alkynyl.

In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG),(IH), (IJ), (IK), or (IL), Y is —COOH or —COOR⁵.

In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG),(IH), (IJ), (IK), or (IL), R⁵ is —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or —C₂-C₆alkynyl. In some embodiments of the compounds of Formula (ID), (IE),(IF), (IG), (IH), (IJ), (IK), or (IL), R⁵ is —C₁-C₃ alkyl, —C₂-C₃alkenyl, or —C₂-C₃ alkynyl.

In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG),(IH), (IJ), (IK), or (IL), p is 3, 4, 5, 6, or 7. In some embodiments, pis 4, 5, 6, or 7.

In some embodiments of the compounds of Formula (ID), (IE), (IF), (IG),(IH), (IJ), (IK), or (IL), one or both of Z¹ and Z² is—W—(CH₂)_(c)—C(R³)(R⁴)—Y, and R³ and R⁴ is independently H, —C₁-C₆alkyl, —C₂-C₆ alkenyl, or —C₂-C₆ alkynyl. In some embodiments of thecompounds of Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL),one or both of Z¹ and Z² is —W—(CH₂)_(c)X(R³)(R⁴)—Y, and Y is —COOH or—COOR⁵. In some embodiments of the compounds of Formula (ID), (IE),(IF), (IG), (IH), (IJ), (IK), or (IL), one or both of Z¹ and Z² is—W—(CH₂)_(c)X(R³)(R⁴)—Y, Y is —COOH or —COOR⁵, and R⁵ is —C₁-C₆ alkyl,—C₂-C₆ alkenyl, or —C₂-C₆ alkynyl. In some embodiments of the compoundsof Formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), or (IL), one orboth of Z¹ and Z² is —W—(CH₂)_(c)X(R³)(R⁴)—Y, Y is —COOH or —COOR⁵, andR⁵ is —C₁-C₃ alkyl, —C₂-C₃ alkenyl, or —C₂-C₃ alkynyl.

In some embodiments of the compound of Formula (IH), (IJ), (IK), or(IL), Q is independently methyl or —OH.

In some embodiments of the compound of Formula (IH), (IJ), (IK), or(IL), t is 1. In some embodiments, t is 2. In some embodiments, t is 3.

In some embodiments, the compound of Formula (IH), (IJ), (IK), or (IL)has any one of the structures shown in Table A-5, Table A-6, or TableA-7, or a pharmaceutically acceptable salt or solvate thereof.

TABLE A-5 Structure

TABLE A-6 Structure

TABLE A-7 Structure Structure

Compounds of Formula (II)

In some embodiments, the compound of the invention is a compound ofFormula (II):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

-   -   each R¹ and R² is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, phenyl or benzyl, or each carbon atom together        with the R¹ and R² attached to the carbon atom independently        form a —C₃-C₇ cycloalkyl group;    -   each n is independently 0, 1, 2, or 3;    -   each m is independently 1, 2, 3, 4, 5, 6, 7, 8 or 9;    -   X is —C(═O)—, —CHR³—, —CH—CH₂(OR³)—, —O—, —S—, —S(═O)—, —S(O)₂—,        —NR³—, —N(OH)—, —N(→O)—, or —Se—;    -   R³ is H, —OH, —O(C₁-C₆ alkyl), —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, —C₃-C₇ cycloalkyl, C₄-C₇ cycloalkenyl, C₅-C₈        cycloalkynyl, phenyl, or benzyl, each —C₁-C₆ alkyl, —C₂-C₆        alkenyl, —C₂-C₆ alkynyl, —C₃-C₇ cycloalkyl, C₄-C₇ cycloalkenyl,        C₅-C₈ cycloalkynyl, phenyl and benzyl being unsubstituted or        substituted with one or more halogen, —CN, —NO₂, or —CF₃ groups;    -   each Y is independently —O—, —NH—, —N(OH)—, —N(→O)—, —S—,        —S(═O)—, —S(O)₂—, or —Se—;    -   each Z is independently —OH, —COOH, —COOR⁵, —SO₃H, —SO₃R⁵,

-   -   each R⁵ is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆        alkynyl, phenyl, or benzyl, each being unsubstituted or        substituted with one or more halogen, —OH, —O(C₁-C₆ alkyl), or        phenyl groups;    -   each R⁶ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl, wherein the —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl is unsubstituted or substituted with one or two        halogen, —OH, —O(C₁-C₆ alkyl), or phenyl groups; and    -   each R⁷ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl.

In some embodiments of compounds of Formula (II), X is —C(═O)—, —CHR³—,—O—, —S—, —S(═O)—, or Se. In some embodiments, X is —C(═O)—, —CH(OH)—,—O—, —S—, —S(═O)—, or Se.

In some embodiments of compounds of Formula (II), R³ is H, —OH, —O(C₁-C₃alkyl), or —C₁-C₃ alkyl.

In some embodiments of compounds of Formula (II), each Y isindependently —O— or —S—.

In some embodiments of compounds of Formula (II), each R¹ and R² isindependently H, —C₁-C₃ alkyl, —C₂-C₃ alkenyl, or —C₂-C₃ alkynyl. Insome embodiments, each R¹ and R² is independently H or methyl.

In some embodiments of compounds of Formula (II), each Z isindependently —COOH or —COOR⁵. In some embodiments, each Z is —COOH.

In some embodiments of compounds of Formula (II), each R⁵ isindependently —C₁-C₃ alkyl, —C₂-C₃ alkenyl, or —C₂-C₃ alkynyl.

In some embodiments of compounds of Formula (II), each n isindependently 0, 1, or 2. In some embodiments, n is 1.

In some embodiments of compounds of Formula (II), each m isindependently 3, 4, 5, or 6. In some embodiments, each m isindependently 4 or 5.

In some embodiments, the compound of Formula (II) has any one of thestructures shown in Table B1, or a pharmaceutically acceptable salt orsolvate thereof.

TABLE B1 Compound No. Structure and Name II-1 

(9-Carboxymethylsulfanyl-5-hydroxy-nonylsulfanyl)-acetic acid II-2 

(11-Carboxymethylsulfanyl-6-hydroxy-undecylsulfanyl)-acetic acid II-3 

(9-Carboxymethylsulfanyl-5-oxo-nonylsulfanyl)-acetic acid II-4 

(11-Carboxymethylsulfanyl-6-oxo-undecylsulfanyl)-acetic acid II-5 

[4-(4-Carboxymethylsulfanyl-butoxy)-butylsulfanyl]-acetic acid II-6 

[5-(5-Carboxymethylsulfanyl-pentyloxy)-pentylsulfanyl]-acetic acid II-7 

(9-Carboxymethoxy-5-hydroxy-nonyloxy)-acetic acid II-8 

(11-Carboxymethoxy-6-hydroxy-undecyloxy)-acetic acid II-9 

(9-Carboxymethoxy-5-oxo-nonyloxy)-acetic acid II-10

(11-Carboxymethoxy-6-oxo-undecyloxy)-acetic acid II-11

[4-(4-Carboxymethoxy-butoxy)-butoxy]-acetic acid II-12

[5-(5-Carboxymethoxy-pentyloxy)-pentyloxy]-acetic acid II-13

[4-(4-Carboxymethylsulfanyl-butylselanyl)-butylsulfanyl]-acetic acidII-14

[5-(5-Carboxymethylsulfanyl-pentylselanyl)-pentylsulfanyl]-acetic acidII-15

[4-(4-Carboxymethoxy-butylselanyl)-butoxy]-acetic acid II-16

[5-(5-Carboxymethoxy-pentylselanyl)-pentyloxy]-acetic acid II-17

[4-(4-Carboxymethylsulfanyl-butylsulfanyl)-butylsulfanyl]-acetic acidII-18

[5-(5-Carboxymethylsulfanyl-pentylsulfanyl)-pentylsulfanyl]-acetic acidII-19

[4-(4-Carboxymethoxy-butylsulfanyl)-butoxy]-acetic acid II-20

[5-(5-Carboxymethoxy-pentylsulfanyl)-pentyloxy]-acetic acid II-21

[4-(4-Carboxymethylsulfanyl-butane-1-sulfinyl)-butylsulfanyl]-aceticacid II-22

[5-(5-Carboxymethylsulfanyl-pentane-1-sulfinyl)-pentylsulfanyl]-aceticacid II-23

[4-(4-Carboxymethoxy-butane-1-sulfinyl)-butoxy]-acetic acid II-24

[5-(5-Carboxymethoxy-pentane-1-sulfinyl)-pentyloxy]-acetic acid

Compounds of Formula (III), (IIIA) and (IIIB)

In some embodiments, the compound of the invention is a compound ofFormula (III):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

-   -   R¹ and R² are independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆        alkynyl, phenyl or benzyl, or R¹ and R² together with the        attached carbon atom form a —C₃-C₇ cycloalkyl group;    -   each m is independently 3, 4, 5, 6, or 7;    -   each n is independently 0, 1, 2, 3, 4, or 5;    -   each q is 0, 1, 2, 3, or 4;    -   X is —O—, —S—, —S(═O)—, —S(O)₂—, —NH—, —N(OH)—, —N(→O)—,        N(alkyl)-, or —N(aryl)-;    -   Z₁ and Z₂ are independently —C₁-C₆ alkyl, —OH, —COOH, —COOR⁵,        —SO₃H, —SO₃R⁵,

-   -   each R⁵ is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆        alkynyl, phenyl, or benzyl, each being unsubstituted or        substituted with one or more halogen, —OH, —O(C₁-C₆ alkyl), or        phenyl groups;    -   each R⁶ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl, wherein the —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl is unsubstituted or substituted with one or two        halogen, —OH, —O(C₁-C₆ alkyl), or phenyl groups; and    -   each R⁷ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl.

In some embodiments, the compound of the invention is a compound ofFormula (III A):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

-   -   R¹ and R² are independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆        alkynyl, phenyl or benzyl, or R¹ and R² together with the        attached carbon atom form a —C₃-C₇ cycloalkyl group;    -   each m is independently 2, 3, 4, 5, 6, or 7;    -   each n is independently 0, 1, 2, 3, 4, or 5;    -   each q is 0, 1, 2, 3, or 4;    -   X is —O—, —S—, —S(═O)—, —S(O)₂—, —NH—, —N(OH)—, —N(→O)—,        N(alkyl)-, or —N(aryl)-;    -   Z₁ and Z₂ are —C₁-C₆ alkyl, —COOH, —COOR⁵, —SO₃R⁵,

wherein Z₁ and Z₂ are the same;

-   -   each R⁵ is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆        alkynyl, phenyl, or benzyl, each being unsubstituted or        substituted with one or more halogen, —OH, —O(C₁-C₆ alkyl), or        phenyl groups;    -   each R⁶ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl, wherein the —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl is unsubstituted or substituted with one or two        halogen, —OH, —O(C₁-C₆ alkyl), or phenyl groups; and    -   each R⁷ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl.

In some embodiments, the compound of the invention is a compound ofFormula (IIIB):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

-   -   R¹ and R² are independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆        alkynyl, phenyl or benzyl, or R¹ and R² together with the        attached carbon atom form a —C₃-C₇ cycloalkyl group;    -   each m is independently 2, 3, 4, 5, 6, or 7;    -   each n is independently 0, 1, 2, 3, 4, or 5;    -   each q is 0, 1, 2, 3, or 4;    -   X is —S—, —S(═O)—, —S(O)₂—, —NH—, —N(OH)—, —N(→O)—, N(alkyl)-,        or —N(aryl)-;    -   Z₁ and Z₂ are independently —C₁-C₆ alkyl, —OH, —COOH, —COOR⁵,        —SO₃H, —SO₃R⁵,

-   -   each R⁵ is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆        alkynyl, phenyl, or benzyl, each being unsubstituted or        substituted with one or more halogen, —OH, —O(C₁-C₆ alkyl), or        phenyl groups;    -   each R⁶ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl, wherein the —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl is unsubstituted or substituted with one or two        halogen, —OH, —O(C₁-C₆ alkyl), or phenyl groups; and    -   each R⁷ is independently H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or        —C₂-C₆ alkynyl.

In some embodiments of compounds of Formula (III) and (IIIB), each Z¹and Z² is independently —OH, —COOH, or —COOR⁵. In some embodiments, eachZ¹ and Z² is independently —C₁-C₆ alkyl.

In some embodiments of compounds of Formula (III), (IIIA), and (IIIB),Z¹ and Z² are the same group: —OH, —COOH, or —COOR⁵. In someembodiments, both Z¹ and Z² is —C₁-C₆ alkyl.

In some embodiments of compounds of Formula (III), X is —S—, —S(═O)—,—S(O)₂—, —NH—, —N(OH)—, —N(→O)—, N(alkyl)-, or —N(aryl)-.

In some embodiments of compounds of Formula (III) and (IIIA), X is O. Insome embodiments of compounds of Formula (III), when X is O, m is 2, 3,5, 6, or 7.

In some embodiments of compounds of Formula (III), (IIIA), and (IIIB),each n is independently 0 or 1. In some embodiments, n is 0. In someembodiments, n is 1.

In some embodiments of compounds of Formula (III), (IIIA), and (IIIB),each m is independently 4, 5, or 6. In some embodiments, m is 5 or 6. Insome embodiments, m is 4. In some embodiments, m is 5. In someembodiments, m is 6. In some embodiments, m is 2 or 3.

In some embodiments of compounds of Formula (III), (IIIA), and (IIIB),R¹ and R² together with the attached carbon atom form a —C₃-C₇cycloalkyl group.

In some embodiments, the compound of Formula (III) or (IIIA) has any oneof the structures shown in Table B2, or a pharmaceutically acceptablesalt or solvate thereof.

TABLE B2 Compound No. Structure and Name III-10

1,1′-(oxybis(propane-3,1-diyl))bis(cyclopropane-1-carboxylic acid)III-11

1-(3-(4-(1-carboxycyclopropyl)butoxy)propyl)cyclopropane-1-carboxylicacid III-12

1-(2-(4-(1-carboxycyclopropyl)butoxy)ethyl)cyclopropane-1-carboxylicacid III-13

1,1′-(oxybis(butane-4,1-diyl))bis(cyclopropane-1-carboxylic acid) III-14

1-(5-(2-(1-carboxycyclopropyl)ethoxy)pentyl)cyclopropane-1-carboxylicacid III-15

1-(3-((5-(1-carboxycyclopropyl)pentyl)oxy)propyl)cyclopropane-1-carboxylicacid III-16

1-(5-(4-(1-carboxycyclopropyl)butoxy)pentyl)cyclopropane-1-carboxylicacid III-17

1,1′-(oxybis(pentane-5,1-diyl))bis(cyclopropane-1-carboxylic acid)III-18

1-(5-((6-(1-carboxycyclopropyl)hexyl)oxy)pentyl)cyclopropane-1-carboxylicacid III-19

1,1′-(oxybis(hexane-6,1-diyl))bis(cyclopropane-1-carboxylic acid) III-20

1-(6-((7-(1-carboxycyclopropyl)heptyl)oxy)hexyl)cyclopropane-1-carboxylicacid III-21

1,1′-(oxybis(heptane-7,1-diyl))bis(cyclopropane-1-carboxylic acid)

Compositions of the Invention

In some embodiments, the composition of the invention comprises (i) aneffective amount of a compound of the invention and (ii) apharmaceutically acceptable carrier or vehicle.

In some embodiments, the composition of the invention comprises (i) aneffective amount of a compound of Formula (IA):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

-   -   each p is independently 1, 2, 3, 4, 5, 6, or 7;    -   Z¹ and Z² is independently —C(R¹)(R²)—(CH₂)_(c)—COOH or        —C(R¹)(R²)—(CH₂)_(c)—COOR⁵;    -   each c is independently 0, 1, 2, or 3;    -   each R¹ and R² is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl,        —C₂-C₆ alkynyl, phenyl or benzyl, or each carbon atom together        with the R¹ and R² attached to the carbon atom independently        form a —C₃-C₇ cycloalkyl group;    -   each R⁵ is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆        alkynyl, phenyl, or benzyl, each being unsubstituted or        substituted with one or more halogen, —OH, —O(C₁-C₆ alkyl), or        phenyl groups; and

(ii) a pharmaceutically acceptable carrier or vehicle.

In some embodiments of the composition comprising a compound of Formula(IA), each R¹ and R² is independently —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or—C₂-C₆ alkynyl. In some embodiments, each R¹ and R² is independently—C₁-C₃ alkyl, —C₂-C₃ alkenyl, or —C₂-C₃ alkynyl. In some embodiments, R¹and R² are methyl.

In some embodiments of the composition comprising a compound of Formula(IA), c is 0 or 1.

In some embodiments of the composition comprising a compound of Formula(IA), R⁵ is —C₁-C₆ alkyl, —C₂-C₆ alkenyl, or —C₂-C₆ alkynyl. In someembodiments, R⁵ is —C₁-C₃ alkyl, —C₂-C₃ alkenyl, or —C₂-C₃ alkynyl.

In some embodiments of the composition comprising a compound of Formula(IA), the compound is Compound I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8,I-9, or 1-10, or a pharmaceutically acceptable salt or solvate thereof,or a compound having the structure

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the composition of the invention comprises aneffective amount of a compound having a structure depicted in TablesA-1, A-2, A-3, or A-4, or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the composition of the invention comprisesan effective amount of a compound having a structure depicted in TableB1, or a pharmaceutically acceptable salt or solvate thereof. In someembodiments, the composition of the invention comprises an effectiveamount of a compound having a structure depicted in Table B2, or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the composition of the invention comprises an effectiveamount of a compound having a structure depicted in Table C, or apharmaceutically acceptable salt or solvate thereof.

TABLE C Compound No. Structure and Name III-1

In some embodiments, the composition of the invention further comprisesanother pharmaceutically active agent.

In some embodiments, the other pharmaceutically active agent is astatin, a thiazolidinedione or fibrate, a bile-acid-binding-resin, aniacin, an anti-obesity drug, a hormone, a tyrophostine, asulfonylurea-based drug, a biguanide, an α-glucosidase inhibitor, anapolipoprotein A-I agonist, apolipoprotein E agonist, aphosphodiesterase type-5 inhibitor, a cardiovascular drug, anHDL-raising drug, an HDL enhancer, an agonist of the apolipoprotein A-Igene or protein, an agonist of the apolipoprotein A-IV gene or protein,an agonist of an apolipoprotein gene, an ATP citrate lyase modulator, anATP citrate lyase allosteric inhibitor, an acetyl-CoA carboxylasemodulator, or an acetyl-CoA carboxylase allosteric inhibitor.

In some embodiments, the other pharmaceutically active agent is anantagonist or an inhibitor of a proinflammatory gene or protein or anagonist of an anti-inflammatory gene or protein. In some embodiments,the other pharmaceutically active agent inhibits or reduces aproinflammatory function or increases an anti-inflammatory function ofIL-6, CRP, TNF-α, MCP-1, MIP-1β, CCR5, CCR2, NF-κB or TGF-β1.

In some embodiments, the other pharmaceutically active agent affects theexpression or function of a fibrosis gene or protein or a mitogenesisgene or protein. In some embodiments, the other pharmaceutically activeagent regulates the expression or function of FGF-21, MMP-2, TIMP-1,ASK1 or Collagen type 3.

In some embodiments, the other pharmaceutically active agent is aregulator of lipid metabolism- or -trafficking-related genes, aregulator of PPAR-α target genes such as, but not limited to, HD(ECHS1), PDK4 and Cyp7A1, a regulator of SGLT1, SGL2, ApoC-III, Sulf-2,ANGPTL3, ANGPTL4 and LPL genes.

In some embodiments, the other pharmaceutically active agent is astatin. In some embodiments, the statin is atorvastatin, simvastatin,pravastatin, rosuvastatin, fluvastatin, lovastatin, pitavastatin,mevastatin, dalvastatin, dihydrocompactin, or cerivastatin, or apharmaceutically acceptable salt thereof. In some embodiments, statin islovastatin.

In some embodiments, the other pharmaceutically active agent is afibrate. In some embodiment, the fibrate is fenofibrate, gemfibrozil, orfenofibric acid.

In some embodiments, the other pharmaceutically active agent issorafenib. In yet some other embodiments, the other pharmaceuticallyactive agent is TAXOL® (paclitaxel). In yet some other embodiments, theother pharmaceutically active agent is carotuximab. In yet some otherembodiments, the other pharmaceutically active agent is pembrolizumab.In yet some other embodiments, the other pharmaceutically active agentis lenvatinib. In yet some other embodiments, the other pharmaceuticallyactive agent is avelumab. In some embodiments, the otherpharmaceutically active agent is durvalumab. In yet some otherembodiments, the other pharmaceutically active agent is tremelimumab. Inyet some other embodiments the other pharmaceutically active agent isnivolumab. In yet some other embodiments the other pharmaceuticallyactive agent is tazemetostat, cemiplimab, ABX196, T-cell receptor (TCR)immune cell therapy agent, such as LioCyx™, TBI-302, namodenoson,MM-310, a tumor-injected oncolytic virus or gene-modified oncolyticvirus such as, but not limited to, telomelysin and imlygic; or animmunomodulating gene-therapy agent such as MDA-7/IL-24, GLIPR1/RTVP-1,and REIC/Dkk-3.

In yet some other embodiments the other pharmaceutically active agent iscenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib,LY2109761, LDE225, nivolumub, firsocostat, apararenone, metformin,Leucine-Metformin-Sildenafil Combination, IMM-124E, RG-125, Vitamin E,cysteamine, selonsertib, losartan, RO5093151, pradigastat, sitagliptin,vildagliptin, NGM282, pegbelfermin, PF-05231023, obeticholic acid,cilofexo, tropifexor, EDP-305, INT-767,galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide,ND-L02-s0201/BMS-986263, volixibat, amlexanox, PF-06835919, leptin,metreleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831,roflumilast, elafibranor, pioglitazone, rosiglitazone, fenofibrate,saroglitazar, lanifibranor, aramchol, ipragliflozin, dapagliflozin,empagliflozin, BI 1467335, rosuvastatin, atorvastatin, pitavastatin,VK2809, MGL-3196, or nalmafene. In some embodiments, the otherpharmaceutically active agent is pentamidine, berberine, L-camitine,EYPOOla, silymarin, miricorilant, ursodeoxycholic acid, metadoxine,ezetimibe, cystadane, L-alanine, saroglitazar magnesium, volixibat,firsocostat, cilofexor, elafibranor, nalmefene, solithromycin,99mTechnetium-Mebrofenin, Tropifexor, S-adenosylmethionine,pentoxifylline, olesoxime, AKR-001, seladelpar, fisogatinib,doxorubicin, cabozantinib, deferoxamine, itacitinib, chiauranib, SF1126,anlotinib, PI 101, varlitinib, SHR-1210, SHR6390, capmatinib,dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527,OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929,guadecitabine, linrodostat, copanlisib, MIV-818, vorolanib, RO7070179,axitinib, sunitinib, zotiraciclib citrate, sintilimab, camrelizumab,spartalizumab, toripalimab, bispecific antibody XmAb20717, mapatumumab,tremelimumab, carotuximab, tocilizumab, ipilimumab, atezolizumab,bevacizumab, ramucirumab, IB1305, ascrinvacumab, sitravatinib,cytokine-based biologic agent IRX-2, bempegaldesleukin, DKN-01,PTX-9908, AK104, PT-112, SRF388, ET1402L1-CART, Glypican 3-specificChimeric Antigen Receptor Expressing T Cells (CAR-T cells),CD147-targeted CAR-T cells, NKG2D-based CAR T-cells, neoantigen reactiveT cells, Pexastimogene Devacirepvec, Talimogene Laherparepvec,GNOS-PV02, INO-9012, ABBV-176, NCI-4650, DNAJB1-PRKACA fusion kinasepeptide vaccine, or IMA970A, novantrone, prednisone, pixantrone,losoxantrone, Cytidine-phosphate-guanosine (CpG) DNA, paclitaxel,oraxol, MTL-CEBPA, ribavirin, elbasvir, grazoprevir, lipotecan, ZSP1241,U3-1784, avadomide, INCAGN01949, or CMP-001.

In some embodiments, the other pharmaceutically active agent is ananti-cancer agent, immunotherapeutic agent, oncologic virus, or vaccine.

In some embodiments, the other pharmaceutically active agent is ananti-cancer agent. In some embodiments, the anti-cancer agent issorafenib, TAXOL® (paclitaxel), lenvatinib, tazemetostat, TBI-302,namodenoson, MM-310, cenicriviroc, elafibranor, eicosapentaenoic acid,galunisertib, LY2109761, LDE225, firsocostat, apararenone, metformin,Leucine-Metformin-Sildenafil Combination, Vitamin E, cysteamine,selonsertib, losartan, RO5093151 pradigastat, sitagliptin, vildagliptin,NGM282, pegbelfermin, PF-05231023, obeticholic acid, cilofexor,tropifexor, EDP-305, INT-767, galactoarabino-rhamnogalacturonate,liraglutide, semaglutide, exenatide, volixibat, amlexanox, PF-06835919,leptin, metreleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602K,ASP9831, roflumilast, elafibranor, pioglitazone, rosiglitazone,fenofibrate, saroglitazar, lanifibranor, aramchol, ipragliflozin,dapagliflozin, empagliflozin, BI 1467335, rosuvastatin, atorvastatin,pitavastatin, VK2809, MGL-3196, nalmafene, pentamidine, berberine,L-camitine, EYPOOla, silymarin, miricorilant, ursodeoxycholic acid,metadoxine, ezetimibe, cystadane, L-alanine, saroglitazar magnesium,volixibat, elafibranor, nalmefene, solithromycin,99mTechnetium-Mebrofenin, S-adenosylmethionine, pentoxifylline,olesoxime, AKR-001, seladelpar, fisogatinib, doxorubicin, cabozantinib,deferoxamine, itacitinib, chiauranib, SF1126, anlotinib, PI 101,varlitinib, SHR-1210, SHR6390, capmatinib, dabrafenib, trametinib,sapanisertib, meclizine, enzalutamide, H3B-6527, OBI-3424, brivanib,tepotinib, temsirolimus, epacadostat, RO7119929, guadecitabine,linrodostat, copanlisib, MIV-818, vorolanib, RO7070179, axitinib,sunitinib, or zotiraciclib citrate.

In some embodiments, the composition of the invention further comprisesan anti-cancer agent.

In some embodiments, the other pharmaceutically active agent is animmunotherapeutic agent. In some embodiments, the immunotherapeuticagent is pembrolizumab, avelumab, durvalumab, nivolumab, cemiplimab,ABX196, sintilimab, camrelizumab, spartalizumab, toripalimab, bispecificantibody XmAb20717, mapatumumab, tremelimumab, carotuximab, tocilizumab,ipilimumab, atezolizumab, bevacizumab, ramucirumab, IBI305,ascrinvacumab, TCR T-cell therapy agent, sitravatinib, cytokine-basedbiologic agent IRX-2, bempegaldesleukin, DKN-01, PTX-9908, AK104,PT-112, SRF388, ET1402L1-CART, Glypican 3-specific Chimeric AntigenReceptor Expressing T Cells (CAR-T cells), CD147-targeted CAR-T cells,NKG2D-based CAR T-cells, or neoantigen reactive T cells.

In some embodiments, the composition of the invention further comprisesan immunotherapeutic agent.

In some embodiments, the other pharmaceutically active agent is anoncologic virus. In some embodiments, the oncologic virus isPexastimogene Devacirepvec or Talimogene Laherparepvec. In someembodiments, the composition of the invention further comprises anoncologic virus.

In some embodiments, the other pharmaceutically active agent is avaccine. In some embodiments, the vaccine is GNOS-PV02, INO-9012,ABBV-176, NCI-4650, DNAJB1-PRKACA fusion kinase peptide vaccine, orIMA970A. In some embodiments, the composition of the invention furthercomprises a vaccine.

In some embodiments, the other pharmaceutically active agent isnovantrone, prednisone, pixantrone, losoxantrone,Cytidine-phosphate-guanosine (CpG) DNA, paclitaxel, oraxol, MTL-CEBPA,ribavirin, elbasvir, grazoprevir, lipotecan, ZSP1241, U3-1784,avadomide, INCAGN01949, or CMP-001.

In some embodiments, the composition of the invention further comprisestwo or more other pharmaceutically active agents. In some embodiments,the two or more other pharmaceutically active agents are oncolyticagents, such as, but not limited to, nanatinostat and valganciclovir.

In some embodiments, the composition of the invention further comprisesa pharmaceutically active agent: sorafenib, TAXOL® (paclitaxel),lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, cenicriviroc,elafibranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225,firsocostat, apararenone, metformin, Leucine-Metformin-SildenafdCombination, Vitamin E, cysteamine, selonsertib, losartan, RO5093151pradigastat, sitagliptin, vildagliptin, NGM282, pegbelfermin,PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767,galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide,volixibat, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab,tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor,pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor,aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI 1467335,rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalmafene,pentamidine, berberine, L-camitine, EYPOOla, silymarin, miricorilant,ursodeoxycholic acid, metadoxine, ezetimibe, cystadane, L-alanine,saroglitazar magnesium, volixibat, elafibranor, nalmefene,solithromycin, 99mTechnetium-Mebrofenin, S-adenosylmethionine,pentoxifylline, olesoxime, AKR-001, seladelpar, fisogatinib,doxorubicin, cabozantinib, deferoxamine, itacitinib, chiauranib, SF1126,anlotinib, PI 101, varlitinib, SHR-1210, SHR6390, capmatinib,dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527,OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929,guadecitabine, linrodostat, copanlisib, MIV-818, vorolanib, RO7070179,axitinib, sunitinib, or zotiraciclib citrate. In some embodiments of thecomposition of the invention, composition comprises (a) Compound I-1,Compound I-32, Compound I-61, or Compound III-1, or a pharmaceuticallyacceptable salt or solvate thereof and (b) a pharmaceutically activeagent: sorafenib, TAXOL® (paclitaxel), lenvatinib, tazemetostat,TBI-302, namodenoson, MM-310, cenicriviroc, elafibranor,eicosapentaenoic acid, galunisertib, LY2109761, LDE225, firsocostat,apararenone, metformin, Leucine-Metformin-Sildenafil Combination,Vitamin E, cysteamine, selonsertib, losartan, RO5093151 pradigastat,sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023,obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767,galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide,volixibat, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab,tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor,pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor,aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI 1467335,rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalmafene,pentamidine, berberine, L-camitine, EYPOOla, silymarin, miricorilant,ursodeoxycholic acid, metadoxine, ezetimibe, cystadane, L-alanine,saroglitazar magnesium, volixibat, elafibranor, nalmefene,solithromycin, 99mTechnetium-Mebrofenin, S-adenosylmethionine,pentoxifylline, olesoxime, AKR-001, seladelpar, fisogatinib,doxorubicin, cabozantinib, deferoxamine, itacitinib, chiauranib, SF1126,anlotinib, PI 101, varlitinib, SHR-1210, SHR6390, capmatinib,dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527,OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929,guadecitabine, linrodostat, copanlisib, MIV-818, vorolanib, RO7070179,axitinib, sunitinib, or zotiraciclib citrate.

In some embodiments of the composition of the invention, compositioncomprises a compound of the invention and a pharmaceutically activeagent: sorafenib, TAXOL® (paclitaxel), carotuximab, pembrolizumab,lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat,cemiplimab, ABX196, T-cell receptor (TCR) immune cell therapy agent,TBI-302, namodenoson, MM-310, tumor-injected oncolytic viruses orgene-modified oncolytic viruses, or immunomodulating gene-therapyagents. In some embodiments, composition comprises (a) Compound I-1,Compound I-32, Compound I-61, or Compound III-1, or a pharmaceuticallyacceptable salt or solvate thereof and (b) a pharmaceutically activeagent is sorafenib, TAXOL® (paclitaxel), carotuximab, pembrolizumab,lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat,cemiplimab, ABX196, T-cell receptor (TCR) immune cell therapy agent,TBI-302, namodenoson, MM-310, tumor-injected oncolytic viruses orgene-modified oncolytic viruses, or immunomodulating gene-therapyagents.

In some embodiments of the composition of the invention, compositioncomprises a compound of the invention and sorafenib or lenvatinib. Insome embodiments, composition comprises (a) Compound I-1, Compound I-32,Compound I-61, or Compound III-1, or a pharmaceutically acceptable saltor solvate thereof and (b) sorafenib or lenvatinib. In some embodiments,composition comprises (a) Compound I-1 or a pharmaceutically acceptablesalt or solvate thereof and (b) sorafenib or lenvatinib. In someembodiments, composition comprises (a) Compound I-32 or apharmaceutically acceptable salt or solvate thereof and (b) sorafenib orlenvatinib. In some embodiments, composition comprises (a) Compound I-32or a pharmaceutically acceptable salt or solvate thereof and (b)sorafenib. In some embodiments, composition comprises (a) Compound I-32or a pharmaceutically acceptable salt or solvate thereof and (b)lenvatinib. In some embodiments, composition comprises (a) Compound I-61or a pharmaceutically acceptable salt or solvate thereof and (b)sorafenib or lenvatinib. In some embodiments, composition comprises (a)Compound I-61 or a pharmaceutically acceptable salt or solvate thereofand (b) sorafenib. In some embodiments, composition comprises (a)Compound I-61 or a pharmaceutically acceptable salt or solvate thereofand (b) lenvatinib. In some embodiments, composition comprises (a)Compound III-1 or a pharmaceutically acceptable salt or solvate thereofand (b) sorafenib or lenvatinib.

Table D sets forth embodiments A1-A4, B1-B4, C₁-C₄, D1-D4, E1-E4, F1-F4,G1-G4, H1-H4, I1-I4, J1-J4, K1-K4, L1-L4, M1-M4, N1-N4, O1-O4, P1-P4,Q1-Q4, R1-R4 and S1-S4. Each embodiment of Table D refers to aparticular compound of invention and another pharmaceutically activeagent. For example, embodiment A1 refers to Compound I-1 (or apharmaceutically acceptable salt or solvate thereof) and sorafenib;embodiment A2 refers to Compound I-32 (or a pharmaceutically acceptablesalt or solvate thereof) and sorafenib; etc. In some embodiments, thecompositions of the invention comprise an effective amount of a compoundof the invention and another pharmaceutically active agent set forth inan embodiment of Table D.

TABLE D Embodiments 1 2 3 4 Compound Compound Compound Compound I-1 or aI-32 or a I-61 or a III-1 or a pharma- pharma- pharma- pharma-ceutically ceutically ceutically ceutically acceptable acceptableacceptable acceptable salt or salt or salt or salt or solvate solvatesolvate solvate thereof thereof thereof thereof A sorafenib A1 A2 A3 A4B lenvatinib B1 B2 B3 B4 C TAXOL® C1 C2 C3 C4 (paclitaxel) D carotuximabD1 D2 D3 D4 E pembrolizumab E1 E2 E3 E4 F avelumab F1 F2 F3 F4 Gdurvalumab G1 G2 G3 G4 H tremelimumab H1 H2 H3 H4 I nivolumab I1 I2 I3I4 J tazemetostat J1 J2 J3 J4 K cemiplimab K1 K2 K3 K4 L ABX196 L1 L2 L3L4 M T-cell receptor M1 M2 M3 M4 (TCR) immune cell therapy N TBI-302 N1N2 N3 N4 O namodenoson O1 O2 O3 O4 P MM-310 P1 P2 P3 P4 Q tumor-injectedQ1 Q2 Q3 Q4 oncolytic virus R gene-modified R1 R2 R3 R4 oncolytic virusS immunomodulating S1 S2 S3 S4 gene-therapy agent

In some embodiments, the pharmaceutically acceptable carrier or vehicleincludes, but is not limited to, a binder, filler, diluent,disintegrant, wetting agent, lubricant, glidant, coloring agent,dye-migration inhibitor, sweetening agent or flavoring agent.

Binders or granulators impart cohesiveness to a tablet to ensure thetablet remaining intact after compression. Suitable binders orgranulators include, but are not limited to, starches, such as cornstarch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500);gelatin; sugars, such as sucrose, glucose, dextrose, molasses, andlactose; natural and synthetic gums, such as acacia, alginic acid,alginates, extract of Irish moss, Panwar gum, ghatti gum, mucilage ofisabgol husks, carboxymethylcellulose, methylcellulose,polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powderedtragacanth, and guar gum; celluloses, such as ethyl cellulose, celluloseacetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxyethylcellulose (HEC),hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC);microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103,AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixturesthereof.

Suitable fillers include, but are not limited to, talc, calciumcarbonate, microcrystalline cellulose, powdered cellulose, dextrates,kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinizedstarch, and mixtures thereof. In some embodiments, the binder ishydroxypropylcellulose.

The binder or filler can be present from about 2% to about 49% by weightof the compositions of the invention provided herein or any range withinthese values. In some embodiments, the binder or filler is present inthe composition of the invention from about 5% to about 15% by weight.In some embodiments, the binder or filler is present in the compositionof the invention at about 5%, 6%, 7%, 8%, 9%, 8%, 10%, 11%, 12%, 13%,14%, or 15% by weight or any range within any of these values.

Suitable diluents include, but are not limited to, dicalcium phosphate,calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose,kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Certain diluents, such as mannitol, lactose, sorbitol, sucrose, andinositol, when present in sufficient quantity, can impart properties tosome compressed tablets that permit disintegration in the mouth bychewing. Such compressed tablets can be used as chewable tablets. Insome embodiments, the diluent is lactose monohydrate. In someembodiments, the diluent is lactose monohydrate Fast-Flo 316 NF.

The compositions of the invention can comprise a diluent, e.g., fromabout 5% to about 49% of a diluent by weight of composition or any rangebetween any of these values. In some embodiments, the diluent is presentin the compositions of the invention from about 15% to about 30% byweight. In some embodiments, the diluent is present in the compositionof the invention at about 15%, 16%, 17%, 18%, 19%, 18%, 20%, 21%, 22%,23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% by weight or any range withinany of these values.

Suitable disintegrants include, but are not limited to, agar; bentonite;celluloses, such as methylcellulose and carboxymethylcellulose; woodproducts; natural sponge; cation-exchange resins; alginic acid; gums,such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses,such as croscarmellose; cross-linked polymers, such as crospovidone;cross-linked starches; calcium carbonate; microcrystalline cellulose,such as sodium starch glycolate; polacrilin potassium; starches, such ascorn starch, potato starch, tapioca starch, and pre-gelatinized starch;clays; aligns; and mixtures thereof. The amount of disintegrant in thecompositions of the invention can vary. In some embodiments, thedisintegrant is croscarmellose sodium. In some embodiments, thedisintegrant is croscarmellose sodium NF (Ac-Di-Sol).

The compositions of the invention can comprise a disintegrant, e.g.,from about 0.5% to about 15% or from about 1% to about 10% by weight ofa disintegrant. In some embodiments, the compositions of the inventioncomprise a disintegrant in an amount of about 5%, 6%, 7%, 8%, 9%, 8%,10%, 11%, 12%, 13%, 14%, or 15% by weight of the composition or in anyrange within any of these values.

Suitable lubricants include, but are not limited to, calcium stearate;magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol;mannitol; glycols, such as glycerol behenate and polyethylene glycol(PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetableoil, including peanut oil, cottonseed oil, sunflower oil, sesame oil,olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyllaureate; agar; starch; lycopodium; silica or silica gels, such asAEROSIL® 200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co.of Boston, Mass.); and mixtures thereof. In some embodiments, thelubricant is magnesium stearate.

The compositions of the invention can comprise a lubricant, e.g., about0.1 to about 5% by weight of a lubricant. In some embodiments, thecompositions of the invention comprise a lubricant in an amount of about0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 0.8%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%,1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%,2.8%, 2.9%, or 3.0%, by weight of the composition or in any range withinany of these values.

Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (CabotCo. of Boston, Mass.), and talc, including asbestos-free talc.

Coloring agents include any of the approved, certified, water solubleFD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate,and color lakes and mixtures thereof.

Flavoring agents include natural flavors extracted from plants, such asfruits, and synthetic blends of compounds that provide a pleasant tastesensation, such as peppermint and methyl salicylate.

Sweetening agents include sucrose, lactose, mannitol, syrups, glycerin,sucralose, and artificial sweeteners, such as saccharin and aspartame.

Suitable emulsifying agents include gelatin, acacia, tragacanth,bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate(TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), andtriethanolamine oleate. Suspending and dispersing agents include sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodiumcarbomethylcellulose, hydroxypropyl methylcellulose, andpolyvinylpyrolidone. Preservatives include glycerin, methyl andpropylparaben, benzoic add, sodium benzoate and alcohol. Wetting agentsinclude propylene glycol monostearate, sorbitan monooleate, diethyleneglycol monolaurate, and polyoxyethylene lauryl ether.

Solvents include glycerin, sorbitol, ethyl alcohol, and syrup.

Examples of non-aqueous liquids utilized in emulsions include mineraloil and cottonseed oil. Organic acids include citric and tartaric acid.Sources of carbon dioxide include sodium bicarbonate and sodiumcarbonate.

The compounds of the invention and the compositions of the invention canbe formulated for administration by a variety of means including orally,parenterally, by inhalation spray, topically, or rectally informulations containing pharmaceutically acceptable carriers, adjuvantsand vehicles. The term “parenteral” as used here includes subcutaneous,intravenous, intramuscular, and intraarterial injections with a varietyof infusion techniques. Intraarterial and intravenous injection as usedherein includes administration through catheters.

The compounds of the invention and the compositions of the invention canbe formulated in accordance with the routine procedures adapted fordesired administration route. Accordingly, the compositions of theinvention can take such forms as suspensions, solutions or emulsions inoily or aqueous vehicles, and can contain formulatory agents such assuspending, stabilizing and/or dispersing agents. The compounds of theinvention and the compositions of the invention can be formulated as apreparation suitable for implantation or injection. Thus, for example,the compositions of the invention can be formulated with suitablepolymeric or hydrophobic materials (e.g., as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly solublederivatives (e.g., as a sparingly soluble salt). The compounds of theinvention and the compositions of the invention can be in powder formfor constitution with a suitable vehicle, e.g., sterile pyrogen-freewater, before use. Suitable formulations for each of these methods ofadministration can be found, for example, in Remington: The Science andPractice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott,Williams & Wilkins, Philadelphia, Pa.

In some embodiments, the compositions of the invention are suitable fororal administration. These compositions can comprise solid, semisolid,gelmatrix or liquid dosage forms suitable for oral administration. Asused herein, oral administration includes buccal, lingual, andsublingual administration. Suitable oral dosage forms include, withoutlimitation, tablets, capsules, pills, troches, lozenges, pastilles,cachets, pellets, medicated chewing gum, granules, bulk powders,effervescent or non-effervescent powders or granules, solutions,emulsions, suspensions, solutions, wafers, sprinkles, elixirs, syrups orany combination thereof. In some embodiments, compositions of theinvention suitable for oral administration are in the form of a tabletor a capsule. In some embodiments, the composition of the invention isin a form of a tablet. In some embodiments, the composition of theinvention is in a form of a capsule. In some embodiments, the compoundof the invention is contained in a capsule.

In some embodiments, capsules are immediate release capsules.Non-limiting example of a capsule is a Coni-Snap® hard gelatin capsule.

The compositions of the invention can be in the form of compressedtablets, tablet triturates, chewable lozenges, rapidly dissolvingtablets, multiple compressed tablets, or enteric-coating tablets,sugar-coated, or film-coated tablets. Enteric-coated tablets arecompressed tablets coated with substances that resist the action ofstomach acid but dissolve or disintegrate in the intestine, thusprotecting the active ingredients from the acidic environment of thestomach. Enteric-coatings include, but are not limited to, fatty acids,fats, phenylsalicylate, waxes, shellac, ammoniated shellac, andcellulose acetate phthalates. Sugar-coated tablets are compressedtablets surrounded by a sugar coating, which can be beneficial incovering up objectionable tastes or odors and in protecting the tabletsfrom oxidation. Film-coated tablets are compressed tablets that arecovered with a thin layer or film of a water-soluble material. Filmcoatings include, but are not limited to, hydroxyethylcellulose, sodiumcarboxymethylcellulose, polyethylene glycol 4000, and cellulose acetatephthalate. A film coating can impart the same general characteristics asa sugar coating. Multiple compressed tablets are compressed tablets madeby more than one compression cycle, including layered tablets, andpress-coated or dry-coated tablets.

In some embodiments, the coating is a film coating. In some embodiments,the film coating comprises Opadry White and simethicone emulsion 30%USP.

In some embodiments, the compound of the invention is contained in atablet. In some embodiments, the compound of the invention is containedin a compressed tablet. In some embodiments, the compound of theinvention is contained in a film-coated compressed tablet. In someembodiments, the compositions of the invention are in the form offilm-coated compressed tablets.

In some embodiments, the compositions of the invention is prepared byfluid bed granulation of the compound of the invention with one or morepharmaceutically acceptable carrier, vehicle, or excipients. In someembodiments, the compositions of the invention prepared by fluid bedgranulation process can provide tablet formulation with goodflowability, good compressibility, fast dissolution, good stability,and/or minimal to no cracking. In some embodiments, the fluid bedgranulation process allows preparation of formulations having high drugloading, such as over 70% or over 75% of a compound of the invention.

The compositions of the invention can be in the form of soft or hardcapsules, which can be made from gelatin, methylcellulose, starch, orcalcium alginate. The hard gelatin capsule, also known as the dry-filledcapsule (DFC), can comprise of two sections, one slipping over theother, thus completely enclosing the active ingredient. The soft elasticcapsule (SEC) is a soft, globular shell, such as a gelatin shell, whichis plasticized by the addition of glycerin, sorbitol, or a similarpolyol. The soft gelatin shells can contain a preservative to preventthe growth of microorganisms. Suitable preservatives are those asdescribed herein, including methyl- and propyl-parabens, and sorbicacid. The liquid, semi solid, and solid dosage forms provided herein canbe encapsulated in a capsule. Suitable liquid and semisolid dosage formsinclude solutions and suspensions in propylene carbonate, vegetableoils, or triglycerides. Capsules containing such solutions can beprepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and4,410,545. The capsules can also be coated as known by those of skill inthe art in order to modify or sustain dissolution of the activeingredient.

The compositions of the invention can be in liquid or semisolid dosageforms, including emulsions, solutions, suspensions, elixirs, and syrups.An emulsion can be a two-phase system, in which one liquid is dispersedin the form of small globules throughout another liquid, which can beoil-in-water or water-in-oil. Emulsions can include a pharmaceuticallyacceptable non-aqueous liquids or solvent, emulsifying agent, andpreservative. Suspensions can include a pharmaceutically acceptablesuspending agent and preservative. Aqueous alcoholic solutions caninclude a pharmaceutically acceptable acetal, such as a di-(loweralkyl)acetal of a lower alkyl aldehyde (the term “lower” means an alkylhaving between 1 and 6 carbon atoms), e.g., acetaldehyde diethyl acetal;and a water-miscible solvent having one or more hydroxyl groups, such aspropylene glycol and ethanol. Elixirs can be clear, sweetened, andhydroalcoholic solutions. Syrups can be concentrated aqueous solutionsof a sugar, for example, sucrose, and can comprise a preservative. For aliquid dosage form, for example, a solution in a polyethylene glycol canbe diluted with a sufficient quantity of a pharmaceutically acceptableliquid carrier, e.g., water, to be measured conveniently foradministration.

The compositions of the invention for oral administration can be alsoprovided in the forms of liposomes, micelles, microspheres, ornanosystems. Miccellar dosage forms can be prepared as described in U.S.Pat. No. 6,350,458.

The compositions of the invention can be provided as non-effervescent oreffervescent, granules and powders, to be reconstituted into a liquiddosage form. Pharmaceutically acceptable carriers and excipients used inthe non-effervescent granules or powders can include diluents,sweeteners, and wetting agents. Pharmaceutically acceptable carriers andexcipients used in the effervescent granules or powders can includeorganic acids and a source of carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms. And, flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The compositions of the invention can be formulated as immediate ormodified release dosage forms, including delayed-, extended, pulsed-,controlled, targeted-, and programmed-release forms.

In some embodiments, the compositions of the invention comprise afilm-coating.

The compositions of the invention can comprise another active ingredientthat does not impair the composition's therapeutic or prophylacticefficacy or can comprise a substance that augments or supplements thecomposition's efficacy.

The tablet dosage forms can comprise the compound of the invention inpowdered, crystalline, or granular form, and can further comprise acarrier or vehicle described herein, including binder, disintegrant,controlled-release polymer, lubricant, diluent, or colorant.

In some embodiments, the compositions of the invention can furthercomprise an excipient such as a diluent, a disintegrant, a wettingagent, a binder, a glidant, a lubricant, or any combination thereof. Insome embodiments, a tablet comprises a binder. And, in some embodiments,the binder comprises microcrystalline cellulose, dibasic calciumphosphate, sucrose, corn starch, polyvinylpyrridone, hydroxypropylcellulose, hydroxymethyl cellulose, or any combination thereof. In otherembodiments, the tablet comprises a disintegrant. In other embodiments,the disintegrant comprises sodium croscarmellose, sodium starchglycolate, or any combination thereof. In other embodiments, the tabletcomprises a lubricant. And, in some embodiments, the lubricant comprisesmagnesium stearate stearic acid, hydrogenated oil, sodium stearylfumarate, or any combination thereof.

In some embodiments, the compositions of the invention are in the formof a tablet that comprises a binder such as any of the binders describedherein.

In some embodiments, the compositions of the invention are in the formof a tablet that comprises a disintegrant such as any of thedisintegrants described herein.

In some embodiments, the compositions of the invention are in the formof a tablet that comprises a lubricant such as any of the lubricantsdescribed herein.

In some embodiments, the compositions of the invention can be in amodified release or a controlled release dosage form. In someembodiments, the compositions of the invention can comprise particlesexhibiting a particular release profile. For example, the composition ofthe invention can comprise a compound of the invention in an immediaterelease form while also comprising a statin or a pharmaceuticallyacceptable salt thereof in a modified release form, both compressed intoa single tablet. Other combination and modification of release profilecan be achieved as understood by one skilled in the art. Examples ofmodified release dosage forms suited for pharmaceutical compositions ofthe instant invention are described, without limitation, in U.S. Pat.Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533;5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556;5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891;5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350;6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548;6,613,358; and 6,699,500.

In some embodiments, the compositions of the invention are amatrix-controlled release dosage form. For example, the compositions ofthe invention can comprise about 300 mg to about 600 mg of a compound ofthe invention provided as a matrix-controlled release form. In someembodiments, a matrix-controlled release form can further compriseanother pharmaceutically active agent. In some embodiments, the releaseprofile of the compound of the invention and of the otherpharmaceutically active agent is the same or different. Suitablematrix-controlled release dosage forms are described, for example, inTakada et al in “Encyclopedia of Controlled Drug Delivery,” Vol. 2,Mathiowitz ed., Wiley, 1999.

In some embodiments, the compositions of the invention comprise fromabout 10 mg to about 400 mg of another pharmaceutically active agent andfrom about 300 mg to about 600 mg of a compound of the invention. Insome embodiments, the compositions of the invention comprise from about10 mg to about 400 mg of the anti-cancer agent and from about 300 mg toabout 600 mg of a compound of the invention. In some embodiment, thecomposition is in a matrix-controlled modified release dosage form.

In some embodiments, the compositions of the invention comprise fromabout 10 mg to about 40 mg of a statin and from about 300 mg to about600 mg of a compound of the invention, wherein the composition is in amatrix-controlled modified release dosage form.

In some embodiments, the matrix-controlled release form comprises anerodible matrix comprising water-swellable, erodible, or solublepolymers, including synthetic polymers, and naturally occurring polymersand derivatives, such as polysaccharides and proteins.

In some embodiments, the erodible matrix of the matrix-controlledrelease form comprises chitin, chitosan, dextran, or pullulan; gum agar,gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans,gum ghatti, guar gum, xanthan gum, or scleroglucan; starches, such asdextrin or maltodextrin; hydrophilic colloids, such as pectin;phosphatides, such as lecithin; alginates; propylene glycol alginate;gelatin; collagen; cellulosics, such as ethyl cellulose (EC),methylethyl cellulose (MEC), carboxymethyl cellulose (CMC),carrrboxymethyl ethyl cellulose (CMEC,) hydroxyethyl cellulose (HEC),hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulosepropionate (CP), cellulose butyrate (CB), cellulose acetate butyrate(CAB), cellulose acetate phthalate (CAP), cellulose acetate trimellitate(CAT), hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS,hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), orethylhydroxy ethylcellulose (EHEC); polyvinyl pyrrolidone; polyvinylalcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide;polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid(EUDRAGIT®, Rohm America, Inc., Piscataway, N.J.);poly(2-hydroxyethyl-methacrylate); polylactides; copolymers ofL-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolicacid copolymers; poly-D-(−)-3-hydroxybutyric acid; or other acrylic acidderivatives, such as homopolymers and copolymers of butylmethacrylate,methylmethacrylate, ethylmethacrylate, ethyl acrylate,(2-dimethylaminoethyl)methacrylate, or (trimethylaminoethyl)methacrylatechloride; or any combination thereof.

In other embodiments, the compositions of the invention are in amatrix-controlled modified release form comprising a non-erodiblematrix. In some embodiments, the statin, the compound of the inventionis dissolved or dispersed in an inert matrix and is released primarilyby diffusion through the inert matrix once administered. In someembodiments, the non-erodible matrix of the matrix-controlled releaseform comprises an insoluble polymer, such as polyethylene,polypropylene, polyisoprene, polyisobutylene, polybutadiene,polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene,polyvinylchloride, a methyl acrylate-methyl methacrylate copolymer, anethylene-vinylacetate copolymer, an ethylene/propylene copolymer, anethylene/ethyl acrylate copolymer, a vinylchloride copolymer with vinylacetate, a vinylidene chloride, an ethylene or a propylene, an ionomerpolyethylene terephthalate, a butyl rubber epichlorohydrin rubber, anethylene/vinyl alcohol copolymer, an ethylene/vinyl acetate/vinylalcohol terpolymer, an ethylene/vinyloxyethanol copolymer, a polyvinylchloride, a plasticized nylon, a plasticized polyethyleneterephthalate,a natural rubber, a silicone rubber, a polydimethylsiloxane, a siliconecarbonate copolymer, or a hydrophilic polymer, such as an ethylcellulose, a cellulose acetate, a crospovidone, or a cross-linkedpartially hydrolyzed polyvinyl acetate; a fatty compound, such as acamauba wax, a microcrystalline wax, or a triglyceride; or anycombination thereof.

The compositions of the invention that are in a modified release dosageform can be prepared by methods known to those skilled in the art,including direct compression, dry or wet granulation followed bycompression, melt-granulation followed by compression.

In some embodiments, the compositions of the invention comprise atablets-in-capsule system, which can be a multifunctional and multipleunit system comprising versatile mini-tablets in a hard gelatin capsule.The mini-tablets can be rapid-release, extended-release, pulsatile,delayed-onset extended-release minitablets, or any combination thereof.In some embodiments, combinations of mini-tablets or combinations ofmini-tablets and minibeads comprising multiple active pharmaceuticalagents can each have specific lag times, of release multiplied pulsatiledrug delivery system (DDS), site-specific DDS, slow-quick DDS,quick/slow DDS and zero-order DDS.

In some embodiments, the compositions of the invention are in anosmotic-controlled release dosage form.

In some embodiments, the osmotic-controlled release device comprises aone-chamber system, a two-chamber system, asymmetric membrane technology(AMT), an extruding core system (ECS), or any combination thereof. Insome embodiments, such devices comprise at least two components: (a) thecore which contains the active pharmaceutical agent(s); and (b) asemipermeable membrane with at least one delivery port, whichencapsulates the core. The semipermeable membrane controls the influx ofwater to the core from an aqueous environment of use so as to cause drugrelease by extrusion through the delivery port(s).

In some embodiments, the core of the osmotic device optionally comprisesan osmotic agent, which creates a driving force for transport of waterfrom the environment of use into the core of the device. One class ofosmotic agents useful in the compositions of invention compriseswater-swellable hydrophilic polymers, which are also referred to as“osmopolymers” or “hydrogels,” including, but not limited to,hydrophilic vinyl and acrylic polymers, polysaccharides such as calciumalginate, polyethylene oxide (PEO), polyethylene glycol (PEG),polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate),poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP),cross-linked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVPcopolymers with hydrophobic monomers such as methyl methacrylate andvinyl acetate, hydrophilic polyurethanes containing large PEO blocks,sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC),hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC),carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodiumalginate, polycarbophil, gelatin, xanthan gum, and sodium starchglycolate.

Another class of osmotic agents useful in the compositions of theinvention comprises osmogens, which are capable of imbibing water toaffect an osmotic pressure gradient across the barrier of thesurrounding coating. Suitable osmogens include, but are not limited to,inorganic salts, such as magnesium sulfate, magnesium chloride, calciumchloride, sodium chloride, lithium chloride, potassium sulfate,potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate,potassium chloride, and sodium sulfate; sugars, such as dextrose,fructose, glucose, inositol, lactose, maltose, mannitol, raffinose,sorbitol, sucrose, trehalose, and xylitol; organic acids, such asascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid,sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid,p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; andmixtures thereof.

Osmotic agents of different dissolution rates can be employed toinfluence how rapidly the compound of the invention dissolves followingadministration. For example, an amorphous sugar, such as Mannogeme EZ(SPI Pharma, Lewes, DE) can be included to provide faster deliveryduring the first couple of hours (e.g., about 1 to about 5 hrs) topromptly produce prophylactic or therapeutic efficacy, and gradually andcontinually release of the remaining amount to maintain the desiredlevel of therapeutic or prophylactic effect over an extended period oftime. In some embodiments, the compound of the invention is releasedfrom the compositions of the invention at such a rate to replace theamount of the compound of the invention metabolized or excreted by thesubject.

The core can also include a wide variety of other excipients andcarriers as described herein to enhance the performance of the dosageform or to promote stability or processing.

Materials useful for forming the semipermeable membrane include variousgrades of acrylics, vinyls, ethers, polyamides, polyesters, andcellulosic derivatives that are water-permeable and water-insoluble atphysiologically relevant pHs or are susceptible to being renderedwater-insoluble by chemical alteration, such as crosslinking. Examplesof suitable polymers useful in forming the coating, include plasticized,unplasticized, and reinforced cellulose acetate (CA), cellulosediacetate, cellulose triacetate, CA propionate, cellulose nitrate,cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CAdimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyloxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan acetate, betaglucan triacetate, acetaldehyde dimethyl acetate, triacetate of locustbean gum, hydroxlated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPGcopolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,poly(acrylic) acids and esters and poly-(methacrylic) acids and estersand copolymers thereof, starch, dextran, dextrin, chitosan, collagen,gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones,polystyrenes, polyvinyl halides, polyvinyl esters and ethers, naturalwaxes, and synthetic waxes.

The semipermeable membranes can also be a hydrophobic microporousmembrane, wherein the pores are substantially filled with a gas and arenot wetted by the aqueous medium but are permeable to water vapor, asdisclosed in U.S. Pat. No. 5,798,119. Such hydrophobic but water-vaporpermeable membrane are typically composed of hydrophobic polymers suchas polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene,polyacrylic acid derivatives, polyethers, polysulfones,polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidenefluoride, polyvinyl esters and ethers, natural waxes, and syntheticwaxes.

The delivery port(s) on the semipermeable membrane can be formedpost-coating by mechanical or laser drilling. Delivery port(s) can alsobe formed in situ by erosion of a plug of water-soluble material or byrupture of a thinner portion of the membrane over an indentation in thecore. In addition, delivery ports can be formed during coating process,as in the case of asymmetric membrane coatings of the type disclosed inU.S. Pat. Nos. 5,612,059 and 5,698,220.

The total amount of the compound of the invention released and therelease rate can substantially be modulated via the thickness andporosity of the semipermeable membrane, the composition of the core, andthe number, size, and position of the delivery ports.

In some embodiments, the pharmaceutical composition in an osmoticcontrolled-release dosage form can further comprise additionalconventional excipients as described herein to promote performance orprocessing of the formulation.

The osmotic controlled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art(see, Remington; The Science and Practice of Pharmacy, supra; Santus andBaker, J. Controlled Release 1995, 35, 1-21; Verma et al., DrugDevelopment and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J.Controlled Release 2002, 79, 7-27).

In some embodiments, the pharmaceutical composition provided herein isformulated as asymmetric membrane technology (AMT) controlled-releasedosage form that comprises an asymmetric osmotic membrane that coats acore comprising the active ingredient(s) and other pharmaceuticallyacceptable excipients. See, U.S. Pat. No. 5,612,059 and WO 2002/17918.The AMT controlled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art,including direct compression, dry granulation, wet granulation, and adip-coating method.

In some embodiments, the pharmaceutical composition provided herein isformulated as ESC controlled-release dosage form that comprises anosmotic membrane that coats a core comprising the compound of theinvention, hydroxylethyl cellulose, and other pharmaceuticallyacceptable excipients.

In some embodiments, the compositions of the invention are a modifiedrelease dosage form that is fabricated as a multiparticulate-controlledrelease dosage form that comprises a plurality of particles, granules,or pellets, microparticulates, beads, microcapsules and microtablets,ranging from about 10 μm to about 3 mm, about 50 μm to about 2.5 mm, orfrom about 100 μm to 1 mm in diameter.

The multiparticulate-controlled release dosage forms can provide aprolonged release dosage form with an improved bioavailability. Suitablecarriers to sustain the release rate of the compound of the inventioninclude, without limitation, ethyl cellulose, HPMC, HPMC-phtalate,colloidal silicondioxide and Eudragit-RSPM.

Compositions of the invention in pellet form can comprise 50-80% (w/w)of a drug and 20-50% (w/w) of microcrystalline cellulose or otherpolymers. Suitable polymers include, but are not limited to,microcrystalline wax, pregelatinized starch and maltose dextrin.

Beads can be prepared in capsule and tablet dosage forms. Beads intablet dosage form can demonstrate a slower dissolution profile thanmicroparticles in capsule form. Microparticle fillers suitable forcompositions and therapeutic or prophylactic methods of the inventioninclude, without limitation, sorbitan monooleate (Span 80), HPMC, or anycombination thereof. Suitable dispersions for controlled release latexinclude, for example, ethyl-acrylate and methyl-acrylate.

In some embodiments, the compositions of the invention are in the formor microcapsules and/or microtablets. In some embodiments, microcapsulescomprise extended release polymer microcapsules containing a statin anda compound of the invention with various solubility characteristics.Extended release polymer microcapsules can be prepared with colloidalpolymer dispersion in an aqueous environment. In other embodiments,microcapsules suitable for the compositions and methods provided hereincan be prepared using conventional microencapsulating techniques(Bodmeier & Wang, 1993).

Such multiparticulates can be made by the processes known to thoseskilled in the art, including wet- and dry-granulation,extrusion/spheronization, roller-compaction, melt-congealing, and byspray-coating seed cores. See, for example, Multiparticulate Oral DrugDelivery; Marcel Dekker: 1994; and Pharmaceutical PelletizationTechnology; Marcel Dekker: 1989. Excipients for such technologies arecommercially available and described in US Pharmacopeia.

Other excipients as described herein can be blended with thecompositions of the invention to aid in processing and forming themultiparticulates. The resulting particles can themselves constitute themultiparticulate dosage form or can be coated by various film-formingmaterials, such as enteric polymers, water-swellable, or water-solublepolymers. The multiparticulates can be further processed as a capsule ora tablet.

In other embodiments, the compositions of the invention are in a dosageform that has an instant releasing component and at least one delayedreleasing component, and is capable of giving a discontinuous release ofthe compound in the form of at least two consecutive pulses separated intime from about 0.1 hour to about 24 hours.

In some embodiments, the compositions of the invention comprise fromabout 1 mg to about 1000 mg of a compound of the invention or any amountranging from and to these values. In some embodiment, the compositionsof the invention comprise from about 1 mg to about 500 mg of a compoundof the invention or any amount ranging from and to these values. In someembodiment, the compositions of the invention comprise from about 1 mgto about 400 mg of a compound of the invention or any amount rangingfrom and to these values.

In other embodiments, the compositions of the invention comprise acompound of the invention in an amount that is a molar equivalent toabout 1 mg to about 1000 mg of a compound of the invention or any amountranging from and to these values. In other embodiments, the compositionsof the invention comprise a compound of the invention in an amount thatis a molar equivalent to about 1 mg to about 500 mg of a compound of theinvention or any amount ranging from and to these values. In otherembodiments, the compositions of the invention comprise a compound ofthe invention in an amount that is a molar equivalent to about 1 mg toabout 400 mg of a compound of the invention or any amount ranging fromand to these values.

In some embodiments, the compositions of the invention comprise acompound of the invention in an amount of about 10 wt % to about 99 wt %of the total weight of the composition of the invention.

Methods of the Invention

The present invention provides methods for treating or preventing adisease, comprising administering to a subject in need thereof aneffective amount of the compound of the invention or the composition ofthe invention, wherein the disease is liver disease or an abnormal livercondition; cancer (such as hepatocellular carcinoma orcholangiocarcinoma); a malignant or benign tumor of the lung, liver,gall bladder, bile duct or digestive tract; an intra- or extra-hepaticbile duct disease; a disorder of lipoprotein; a lipid-and-metabolicdisorder; cirrhosis; fibrosis; a disorder of glucose metabolism; acardiovascular or related vascular disorder; a disease resulting fromsteatosis, fibrosis, or cirrhosis; a disease resulting from steatosis,fibrosis, and cirrhosis; a disease associated with increasedinflammation (such as hepatic inflammation or pulmonary inflammation);hepatocyte ballooning; a peroxisome proliferator activatedreceptor-associated disorder; an ATP citrate lyase disorder; anacetyl-coenzyme A carboxylase disorder; obesity; pancreatitis; or renaldisease.

The present invention provides methods for treating or preventing adisease, comprising administering to a subject in need thereof aneffective amount of the compound of the invention or the composition ofthe invention, wherein the disease is cancer, a lipid-and-metabolicdisorder, a liver disorder, cirrhosis, fibrosis, a disorder of glucosemetabolism, a peroxisome proliferator activated receptor-associateddisorder, a malignant or benign tumor of the lung, liver, bile anddigestive tract, an ATP citrate lyase disorder, an acetyl-coenzyme Acarboxylase disorder, obesity, pancreatitis, renal disease, hepatocyteballooning, hepatic inflammation, or pulmonary inflammation.

In some embodiments of the methods as disclosed herein, the disease iscancer. In some embodiments, the cancer is hepatocellular carcinoma(HCC), HCC with cirrhosis, HCC without cirrhosis, cholangiocarcinoma,colorectal cancer, biliary cancer, or pulmonary cancer. In someembodiments, the cancer is fibrosarcoma, myxosarcoma, liposarcoma,chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma,endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma,synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma,rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer,pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostatecancer, esophogeal cancer, stomach cancer, oral cancer, nasal cancer,throat cancer, squamous cell carcinoma, basal cell carcinomaadenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma,papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma,medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma,hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonalcarcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicularcancer, small cell lung carcinoma, bladder carcinoma, lung cancer,epithelial carcinoma, glioma, glioblastoma, multiforme, astrocytoma,medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, skincancer, melanoma, neuroblastoma, retinoblastoma, acute lymphoblasticB-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblasticleukemia (AML), acute promyelocytic leukemia (APL), acute monoblasticleukemia, acute erythroleukemic leukemia, acute megakaryoblasticleukemia, acute myelomonocytic leukemia, acute nonlymphocyctic leukemia,acute undifferentiated leukemia, chronic myelocytic leukemia (CML),chronic lymphocytic leukemia (CLL), hairy cell leukemia, multiplemyeloma, lymphoblastic leukemia, myelogenous leukemia, lymphocyticleukemia, myelocytic leukemias, Hodgkin's disease, non-Hodgkin'slymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, heavy chaindisease, gastrointestinal cancer, head-and-neck cancer, hematopoieticcancer, or polycythemia vera.

In some embodiments, gastrointestinal (digestive) cancer isgastrointestinal stromal tumor (GIST), esophagueal cancer, gallbladdercancer, gastrointestinal carcinoid tumor, cholangiocarcinoma, duodenalcancer, gastroesophageal (ge) junction cancer, islet cell cancer,lpancreatic cancer, stomach cancer, colon cancer, rectal cancer,colorectal cancer, anal cancer, liver cancer, biliary cancer, bile ductcancer, cancer of the small intestine, seudomyxoma peritonei, smallbowel cancer, or cancer of unknown primary.

In some embodiments, the hematopoietic cancer is non-Hodgkin's lymphoma(NHL), Burkitt's lymphoma (BL), multiple myeloma (MM), B chroniclymphocytic leukemia (B-CLL), B and T acute lymphocytic leukemia (ALL),T cell lymphoma (TCL), acute myeloid leukemia (AML), hairy cell leukemia(HCL), Hodgkin's Lymphoma (HL), or chronic myeloid leukemia (CML).

In some embodiments of the methods as disclosed herein, the cancer is inany stage. In some embodiments, the cancer can be in stage 0, stage I,stage II, stage III, or stage IV. In some embodiments of the methods asdisclosed herein, the disease is tumor and the tumor can be in anystage. In some embodiments, the tumor is grade 1, grade 2, grade 3, orgrade 4.

In some embodiments of the methods as disclosed herein, the disease is alipid-and-metabolic disorder. In some embodiments, thelipid-and-metabolic disorder is characterized by high C-reactive protein(CRP), high serum amyloid A (SAA), high alanine aminotransferase (ALT),high aspartate aminotransferase (AST), high alkaline phosphatase (ALP),high gamma-glutamyl transferase (GGT), high low-density lipoprotein(LDL), high very-low-density lipoprotein (VLDL), high apolipoprotein B(ApoB) and ApoB/Lp(a) (lipoprotein(a)) ratio, high total cholesterol,low high-density lipoprotein (HDL), or high non-HDL-cholesterol in thesubject's plasma or blood serum; or by high glucose and insulinresistance in a subject with diabetes. In some embodiments, thelipid-and-metabolic disorder is non-alcoholic fatty liver disease(NAFLD), non-alcoholic steatohepatitis (NASH), or alcoholicsteatohepatitis (ASH).

In some embodiments of the methods as disclosed herein, the disease is adisorder of glucose metabolism. In some embodiments, the disorder ofglucose metabolism is type I diabetes or type II diabetes.

In some embodiments of the methods as disclosed herein, the disease is adisease resulting from steatosis, fibrosis, and cirrhosis. In someembodiment, the disease resulting from steatosis is inflammation. Insome embodiment, the disease resulting from steatosis is NAFLD, NASH, orASH. In some embodiment, the disease resulting from fibrosis is livercirrhosis or liver failure. In some embodiment, the disease resultingfrom cirrhosis is, hepatocellular carcinoma, liver damage, or hepaticencephalopathy.

The present invention provides methods for reducing a concentration in asubject's blood plasma or blood serum the subject's C-reactive protein(CRP) concentration, serum amyloid A (SAA) concentration, alanineaminotransferase (ALT) concentration, aspartate aminotransferase (AST)concentration, alkaline phosphatase (ALP) concentration, gamma-glutamyltransferase (GGT) concentration, serum creatinine concentration,7α-hydroxy-4-cholesten-3-one (C4) concentration, protein:creatinineratio, creatine kinase concentration, angiopoietin-like protein 3concentration, angiopoietin-like protein 4 concentration,angiopoietin-like protein 8 concentration, fibrinogen concentration,total cholesterol concentration, low-density lipoprotein cholesterolconcentration, low-density lipoprotein concentration, very low-densitylipoprotein cholesterol concentration, very low-density lipoproteinconcentration, non-HDL cholesterol concentration, non-HDL concentration,apolipoprotein B concentration, lipoprotein(a) concentration, or serumtriglyceride concentration, comprising administering to a subject inneed thereof an effective amount of the compound of the invention or thecomposition of the invention.

The present invention provides methods for reducing triglycerideconcentration in a subject's liver, comprising administering to asubject in need thereof an effective amount of the compound of theinvention or the composition of the invention.

The present invention provides methods for elevating in a subject'sblood plasma or blood serum a concentration of high-density lipoproteincholesterol or high-density lipoprotein, comprising administering to asubject in need thereof an effective amount of a compound of theinvention or the composition of the invention.

The present invention provides methods for increasing functionalizationof the high-density lipoprotein cholesterol, without increasing itsconcentration in a subject's blood plasma or blood serum, comprisingadministering to a subject in need thereof an effective amount of acompound of the invention or the composition of the invention, whereinan amount or rate of excretion of cholesterol and triglyceridesincreases.

The present invention provides methods for treating a disease,comprising administering to a subject in need thereof an effectiveamount of the compound of the invention or the composition of theinvention, wherein the disease is gastrointestinal disease, irritablebowel syndrome (IBS), inflammatory bowel disease (IBD), or autoimmunedisease.

In some embodiments of the methods as disclosed herein, the disease isinflammatory bowel disease. In some embodiments, the inflammatory boweldisease is Crohn's Disease or ulcerative colitis.

In some embodiments of the methods as disclosed herein, the disease isautoimmune disease. In some embodiments, the autoimmune disease issystemic lupus erythematosus.

The present invention provides methods for regressing, reducing the rateof progression or inhibiting progression of fibrosis, hepatocyteballooning or hepatic inflammation, comprising administering to asubject in need thereof an effective amount of the compound of theinvention or the composition of the invention.

The present invention provides methods for inhibiting, reducing, ordelaying advancement of a subject's lipid synthesis, liver steatosis,hepatocyte ballooning or inflammation, liver fibrosis, lung fibrosis, orcirrhosis, comprising administering to a subject in need thereof aneffective amount of the compound of the invention or the composition ofthe invention.

The present invention provides methods for reducing a subject's risk ofdeveloping or having atherosclerosis, coronary heart disease, peripheralvascular disease, stroke, or restenosis, comprising administering to asubject in need thereof an effective amount of a compound of theinvention.

The present invention provides methods for elevating HDL concentrationin the subject's blood serum or plasma, comprising administering to asubject in need thereof an effective amount of the compound of theinvention or the composition of the invention.

The present invention provides methods for inhibiting NF-kB or stellatecell activation, comprising administering to a subject in need thereofan effective amount of the compound of the invention or the compositionof the invention.

The present invention provides methods for activating PPAR (peroxisomeproliferator-activated receptor) in a subject, comprising administeringto a subject in need thereof an effective amount of the compound of theinvention or the composition of the invention.

The present invention provides methods for CCR2/CCR5 genedownregulation, comprising administering to a subject in need thereof aneffective amount of a compound of the invention.

The present invention provides methods for inhibiting one or more ofNF-kB activation, CCR2 activation, CCR5 activation, and stellate cellactivation, comprising administering to a subject in need thereof aneffective amount of the compound of the invention or the composition ofthe invention.

The present invention provides methods for inhibiting an interleukin'sactivation or concentration, comprising administering to a subject inneed thereof an effective amount of a compound of the invention or thecomposition of the invention. In some embodiments, the interleukin (IL)is IL-2, IL-6, IL-17 or IL-18.

The present invention provides methods for inhibiting fibrin/fibrinogen,gastrin, lactate dehydrogenase, prostatic acid phosphatase (PAP),thyroglobulin, urine catecholamine, urine vanillylmandelic acid (VMA) orurine homovanillic acid (HVA), comprising administering to a subject inneed thereof an effective amount of a compound of the invention or thecomposition of the invention.

The present invention provides methods for inhibiting beta-humanchorionic gonadotropin (beta-hCG), beta-2-microglobulin (B2M), B-cellimmunoglobulin, comprising administering to a subject in need thereof aneffective amount of a compound of the invention or the composition ofthe invention.

The present invention provides methods for inhibiting alpha-fetoprotein(AFP), comprising administering to a subject in need thereof aneffective amount of a compound of the invention or the composition ofthe invention.

The present invention also provides methods for inhibiting hepatic fattyacid or sterol synthesis, comprising administering to a subject in needthereof an effective amount of the compound of the invention or thecomposition of the invention.

The present invention also provides methods for treating or preventing adisease or disorder that is capable of being treated or prevented byincreasing HDL levels, comprising administering to a subject in needthereof an effective amount of the compound of the invention or thecomposition of the invention.

The present invention also provides methods for treating or preventing adisease or disorder that is capable of being treated or prevented bylowering LDL levels, which comprises administering to a subject in needthereof an effective amount of the compound of the invention or thecomposition of the invention.

Without being limited by theory, it is believed that the compounds ofthe invention favorably alter lipid metabolism at least in part byenhancing oxidation of fatty acids through the ACC/malonyl-CoA/CPT-Iregulatory axis. Accordingly, the invention also provides methods fortreating or preventing a metabolic syndrome disorder, comprisingadministering to a subject in need thereof an effective amount of acompound of the invention or composition of the invention.

The present invention further provides methods for modulating, directlyinhibiting or allosterically inhibiting ATP citrate lyase in a subject,comprising administering to the subject an effective amount of acompound of the invention or composition of the invention.

The present invention further provides methods for modulating, directlyinhibiting or allosterically inhibiting acetyl-CoA carboxylase 1 (ACC1)or acetyl-CoA carboxylase 2 (ACC2) in a subject, comprisingadministering to the subject an effective amount of a compound of theinvention or composition of the invention.

The present invention further provides methods for reducing the fat orcholesterol content of livestock meat or poultry eggs, comprisingadministering to the livestock or poultry an effective amount of thecompound of the invention or the composition of the invention.

In some embodiments of the methods as disclosed herein, the compound ofthe invention is administered to the subject in need thereof in therange from about 1 mg to about 1000 mg or any amount ranging from and tothese values. In some embodiment, the compound of the invention isadministered to the subject in need thereof in the rage from about 1 mgto about 900 mg, about 1 mg to about 800 mg, about 1 mg to about 700 mg,about 1 mg to about 600 mg, about 1 mg to about 500 mg, about 1 mg toabout 400 mg, or about 1 mg to about 300 mg.

In some embodiments of the methods as disclosed herein, the compound ofthe invention is administered to the subject in need thereof in a dailydose ranging from about 1 mg to about 1000 mg or any amount ranging fromand to these values. In some embodiments, the compound of the inventionis administered to the subject in need thereof at a daily dose of about1000 mg, about 950 mg, about 900 mg, about 850 mg, about 800 mg, about750 mg, about 700 mg, about 650 mg, about 600 mg, about 550 mg, about500 mg, about 450 mg, about 400 mg, about 350 mg, about 300 mg, about250 mg, about 200 mg, about 150 mg, about 100 mg, about 80 mg, about 60mg, about 40 mg, about 20 mg, about 10 mg, about 5 mg, or about 1 mg.

In some embodiments of the methods as disclosed herein, the compound ofthe invention is administered to the subject in need thereof once a dayat a dose of about 1 mg to about 1000 mg or any amount ranging from andto these values.

In some embodiments of the methods as disclosed herein, the compound ofthe invention is administered to the subject in need thereof twice aday, each dose comprising the compound of the invention in about 1 mg toabout 500 mg or any amount ranging from and to these values. In someembodiment, the compound of the invention is administered to the subjectin need thereof twice a day, each dose comprising the compound of theinvention in about 500 mg, about 450 mg, about 400 mg, about 350 mg,about 300 mg, about 250 mg, about 200 mg, about 150 mg, about 100 mg,about 80 mg, about 60 mg, about 40 mg, about 20 mg, about 10 mg, about 5mg, or about 1 mg.

In some embodiments of the methods as disclosed herein, the compound ofthe invention is administered to the subject in need thereof three timesa day, each dose comprising the compound of the invention in about 1 mgto about 400 mg or any amount ranging from and to these values. In someembodiment, the compound of the invention is administered to the subjectin need thereof three times a day, each dose comprising the compound ofthe invention in about 400 mg, about 350 mg, about 300 mg, about 250 mg,about 200 mg, about 150 mg, about 100 mg, about 80 mg, about 60 mg,about 40 mg, about 20 mg, about 10 mg, about 5 mg, or about 1 mg.

In some embodiments of the methods as disclosed herein, the methodsfurther comprise administering an effective amount of anotherpharmaceutically active agent. In some embodiments, the otherpharmaceutically active agent is administered concurrently orsequentially with (prior or subsequent to) the administration of thecompound of the invention or the composition of the invention. In someembodiments, the other pharmaceutically active agent is a statin, athiazolidinedione or fibrate, a bile-acid-binding-resin, a niacin, ananti-obesity drug, a hormone, a tyrophostine, a sulfonylurea-based drug,a biguanide, an α-glucosidase inhibitor, an apolipoprotein A-I agonist,apolipoprotein E agonist; a phosphodiesterase type-5 inhibitor, acardiovascular drug, an HDL-raising drug, an HDL enhancer, a regulatorof the apolipoprotein A-I gene, a regulator of the apolipoprotein A-IVgene, a regulator of the apolipoprotein gene, an ATP citrate lyasemodulator, an ATP citrate lyase allosteric inhibitor, an acetyl-CoAcarboxylase modulator, or an acetyl-CoA carboxylase allostericinhibitor. In some embodiments, the other pharmaceutically active agentis lovastatin. In some embodiments, the other pharmaceutically activeagent is sorafenib; TAXOL® (paclitaxel); carotuximab; pembrolizumab;lenvatinib; avelumab; durvalumab; tremelimumab; nivolumab; tazemetostat;cemiplimab; ABX196; T-cell receptor (TCR) immune cell therapy agent;TBI-302; namodenoson; MM-310; a tumor-injected oncolytic virus orgene-modified oncolytic virus such as, but not limited to, telomelysinand imlygic; or an immunomodulating gene-therapy agent such asMDA-7/IL-24, GLIPR1/RTVP-1, and REIC/Dkk-3.

In some embodiments of the methods as disclosed herein, the methodsfurther comprises administering two or more other pharmaceuticallyactive agents. In some embodiments, the methods of the inventioncomprise administering two or more other pharmaceutically active agents,optionally in combination. In some embodiments, the two or more otherpharmaceutically active agents are oncolytic agents, such as, but notlimited to, nanatinostat and valganciclovir. In other embodiments, themethods of the invention comprise orally administering a compound of theinvention and further comprise administering a tumor-injected oncolytictreatment. In some embodiments, the combination is administered orally.

In some embodiments, the other pharmaceutically active agent iscenicriviroc, elafibranor, eicosapentaenoic acid, galunisertib,LY2109761, LDE225, nivolumub, firsocostat, apararenone, metformin,leucine-metformin-sildenafil combination (NS-0200), IMM-124E, RG-125,vitamin E, cysteamine, selonsertib, losartan, RO5093151, pradigastat,sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023,obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767,galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide,ND-L02-s0201/BMS-986263, volixibat, amlexanox, PF-06835919, leptin,metreleptin, simtuzumab, tipelukast, oltipraz, MSDC-0602K, ASP9831,roflumilast, elaflbranor, pioglitazone, rosiglitazone, fenofibrate,saroglitazar, laniflbranor, aramchol, ipragliflozin, dapagliflozin,empagliflozin, BI 1467335, rosuvastatin, atorvastatin, pitavastatin,VK2809, MGL-3196, nalmafene, pentamidine, berberine, L-camitine,EYPOOla, silymarin, miricorilant, ursodeoxycholic acid, metadoxine,ezetimibe, cystadane, L-alanine, saroglitazar magnesium, volixibat,solithromycin, 99m technetium-mebrofenin, tropifexor,S-adenosylmethionine, pentoxifylline, olesoxime, AKR-001, or seladelpar.

In some embodiments of the methods as disclosed herein, the methods fortreating or preventing a disease comprise administering Compound I-1,Compound I-32, Compound I-61, or Compound III-1, or a pharmaceuticallyacceptable salt or solvate thereof.

In some embodiments of the methods as disclosed herein, the methods fortreating or preventing a disease comprise administering an effectiveamount of (a) a compound of the invention and (b) anotherpharmaceutically active agent that is sorafenib, TAXOL® (paclitaxel),lenvatinib, tazemetostat, TBI-302, namodenoson, MM-310, cenicriviroc,elaflbranor, eicosapentaenoic acid, galunisertib, LY2109761, LDE225,firsocostat, apararenone, metformin, Leucine-Metformin-SildenafilCombination, Vitamin E, cysteamine, selonsertib, losartan, RO5093151pradigastat, sitagliptin, vildagliptin, NGM282, pegbelfermin,PF-05231023, obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767,galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide,volixibat, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab,tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elaflbranor,pioglitazone, rosiglitazone, fenofibrate, saroglitazar, laniflbranor,aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI 1467335,rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalmafene,pentamidine, berberine, L-carnitine, EYPOOla, silymarin, miricorilant,ursodeoxycholic acid, metadoxine, ezetimibe, cystadane, L-alanine,saroglitazar magnesium, volixibat, elaflbranor, nalmefene,solithromycin, 99mTechnetium-Mebrofenin, S-adenosylmethionine,pentoxifylline, olesoxime, AKR-001, seladelpar, fisogatinib,doxorubicin, cabozantinib, deferoxamine, itacitinib, chiauranib, SF1126,anlotinib, PI 101, varlitinib, SHR-1210, SHR6390, capmatinib,dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527,OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929,guadecitabine, linrodostat, copanlisib, MIV-818, vorolanib, RO7070179,axitinib, sunitinib, or zotiraciclib citrate. In some embodiments of themethods as disclosed herein, the method for treating or preventing adisease comprise administering an effective amount of (a) Compound I-1,Compound I-32, Compound I-61, or Compound III-1, or a pharmaceuticallyacceptable salt or solvate thereof and (b) another pharmaceuticallyactive agent that is sorafenib, TAXOL® (paclitaxel), lenvatinib,tazemetostat, TBI-302, namodenoson, MM-310, cenicriviroc, elafibranor,eicosapentaenoic acid, galunisertib, LY2109761, LDE225, firsocostat,apararenone, metformin, Leucine-Metformin-Sildenafil Combination,Vitamin E, cysteamine, selonsertib, losartan, RO5093151 pradigastat,sitagliptin, vildagliptin, NGM282, pegbelfermin, PF-05231023,obeticholic acid, cilofexor, tropifexor, EDP-305, INT-767,galactoarabino-rhamnogalacturonate, liraglutide, semaglutide, exenatide,volixibat, amlexanox, PF-06835919, leptin, metreleptin, simtuzumab,tipelukast, oltipraz, MSDC-0602K, ASP9831, roflumilast, elafibranor,pioglitazone, rosiglitazone, fenofibrate, saroglitazar, lanifibranor,aramchol, ipragliflozin, dapagliflozin, empagliflozin, BI 1467335,rosuvastatin, atorvastatin, pitavastatin, VK2809, MGL-3196, nalmafene,pentamidine, berberine, L-camitine, EYPOOla, silymarin, miricorilant,ursodeoxycholic acid, metadoxine, ezetimibe, cystadane, L-alanine,saroglitazar magnesium, volixibat, elafibranor, nalmefene,solithromycin, 99mTechnetium-Mebrofenin, S-adenosylmethionine,pentoxifylline, olesoxime, AKR-001, seladelpar, fisogatinib,doxorubicin, cabozantinib, deferoxamine, itacitinib, chiauranib, SF1126,anlotinib, PI 101, varlitinib, SHR-1210, SHR6390, capmatinib,dabrafenib, trametinib, sapanisertib, meclizine, enzalutamide, H3B-6527,OBI-3424, brivanib, tepotinib, temsirolimus, epacadostat, RO7119929,guadecitabine, linrodostat, copanlisib, MIV-818, vorolanib, RO7070179,axitinib, sunitinib, or zotiraciclib citrate.

In some embodiments of the methods as disclosed herein, the methods fortreating or preventing a disease comprise administering an effectiveamount of (a) a compound of the invention and (b) anotherpharmaceutically active agent that is sorafenib, TAXOL® (paclitaxel),carotuximab, pembrolizumab, lenvatinib, avelumab, durvalumab,tremelimumab, nivolumab, tazemetostat, cemiplimab, ABX196, T-cellreceptor (TCR) immune cell therapy agent, TBI-302, namodenoson, MM-310,a tumor-injected oncolytic virus, a gene-modified oncolytic virus, or animmunomodulating gene-therapy agent. In some embodiments of the methodsas disclosed herein, the methods for treating or preventing a diseasecomprise administering an effective amount of (a) Compound I-1, CompoundI-32, Compound I-61, or Compound III-1, or a pharmaceutically acceptablesalt or solvate thereof and (b) another pharmaceutically active agentthat is sorafenib, TAXOL® (paclitaxel), carotuximab, pembrolizumab,lenvatinib, avelumab, durvalumab, tremelimumab, nivolumab, tazemetostat,cemiplimab, ABX196, T-cell receptor (TCR) immune cell therapy agent,TBI-302, namodenoson, MM-310, a tumor-injected oncolytic virus, agene-modified oncolytic virus, or an immunomodulating gene-therapyagent.

In some embodiments, the methods of the invention comprise administeringto a subject in need thereof an effective amount of a compound of theinvention and another pharmaceutically active agent set forth of anembodiment of Table D. In some embodiments, the other pharmaceuticallyactive agent is administered concurrently with, prior to or subsequentto the administration of the compound of the invention or thecomposition of the invention.

In some embodiments of the methods as disclosed herein, the methodsfurther comprise administering radiation therapy to the subject. In someembodiments, the radiation therapy is gamma ray radiation therapy orx-ray radiation therapy. In some embodiments, the radiation therapy isadministered via a gamma ray or x-ray radiation apparatus.

In some embodiments, the radiation therapy is administered concurrentlywith, prior to or subsequent to the administration of the compound ofthe invention or the composition of the invention. In some embodiments,the radiation therapy is administered prior to or subsequent to theadministration of the compound of the invention or the composition ofthe invention.

Methods for Making the Compounds of the Invention

Synthesis and General Protocols

The compounds of Formulae (IA), (IB), (IC), (ID), (IE), (IF), (IG),(IH), (IJ), (IK), and (IL), (collectively “Formula (I)”) can be preparedvia the synthetic methodologies illustrated in Schemes 1-7. The startingmaterials useful for preparing the compounds of the invention andintermediates thereof are commercially available or can be prepared fromcommercially available materials using known synthetic methods andreagents.

In Scheme 1, A can be halogen, such as Cl, Br, or I. In someembodiments, A is Br. In Scheme 1, B can be carbanions of esters ofcarboxylic or malonic esters. In Scheme 1, Q¹ and Q² can eachindependently be —O-alkyl, —S-alkyl, —S-aryl, —NR^(1A)R^(2A), NHR^(1A),phenoxy, aryloxy, benzyl, aryl, cycloalkyl, F, Cl, Br, I, —CF₃,—COR^(1A), heteroaryl, or heterocyclyl, or each carbon atom togetherwith the Q¹ and Q² attached to the carbon atom independently form aheterocyclyl or a carbocyclyl group. R^(1A) and R^(2A) are as definedherein for formula (I).

In Scheme 2, Q¹ and Q² can each independently be —O-alkyl, —S-alkyl,—S-aryl, —NR^(1A)R^(2A), NHR^(1A), phenoxy, aryloxy, benzyl, aryl,cycloalkyl, F, Cl, Br, I, —CF₃, —COR^(1A), heteroaryl, or heterocyclyl,or each carbon atom together with the Q¹ and Q² attached to the carbonatom independently form a heterocyclyl or a carbocyclyl group. R^(1A)and R^(2A) are as defined herein for formula (I)

In Scheme 3, Q¹ and Q² can each independently be —O-alkyl, —S-alkyl,—S-aryl, —NR^(1A)R^(2A), NHR^(1A), phenoxy, aryloxy, benzyl, aryl,cycloalkyl, F, Cl, Br, I, —CF₃, —COR^(1A), heteroaryl, or heterocyclyl,or each carbon atom together with the Q¹ and Q² attached to the carbonatom independently form a heterocyclyl or a carbocyclyl group. R^(1A)and R^(2A) are as defined herein for formula (I).

Scheme 3 illustrates the transformation of ortho, meta, or paraco-haloalkyl substituted arenes of the formula 5, wherein p is aninteger in the range of 2-5 and Hal is Cl, Br, or I, to dicarboxylicacids of the formula 7, wherein R¹ and R² are alkyl and/or aryl moietiesor are connected in a three- to seven-membered cycle. Thistransformation can be accomplished by two different, however relatedpathways. According to the first method, esters of the formulaR¹R²CHCO₂R⁵, wherein R¹ and R² are alkyl and/or aryl moieties or areconnected in a three- to seven-membered cycle and R⁵ is typically ethylor methyl, are deprotonated by strong bases, preferably, but not limitedto, butyl lithium or lithium diisopropylamide, and then reacted withdihalides of the formula 5 to furnish the corresponding diesters of theformula 6. Generally, the reaction is performed at temperatures fromabout −78° C. to about 25° C. and the reaction solvent is preferably THFor diethyl ether (see Larock, R. C. Comprehensive OrganicTransformations. A Guide to Functional Group Preparations, 2^(nd) ed.;Wiley-VCH, New York, 1999, pp 1725-1726 for a discussion of the scope ofthis method. See, Dasseux et al., U.S. Pat. Nos. 6,646,170 and6,410,802, Oniciu et al. U.S. Pat. No. 10,227,285 and Ackerley et al, J.Med. Chem. 1995, 38, 1608-1628 for specific examples of this method). Inthe second step, a diester of the formula 6 is saponified (see Larock,R. C. Comprehensive Organic Transformations. A Guide to Functional GroupPreparations, 2^(nd) ed.; Wiley-VCH, New York, 1999, pp 1959-1968 andSmith, M. B.; March, J. March's Advanced Organic Chemistry. Reactions,Mechanisms, and Structure, 5^(th) ed.; John Wiley and Sons, New York,2001, pp 469-474 for an overview) to a diacid of the formula 7. As analternative, this transformation of a dihalide of the formula 5 to adiacid of the formula 7 can also be achieved in one step, when acarboxylic acid of the formula R¹R²CHCO₂H, wherein R¹ and R² are alkyland/or aryl, is deprotonated twice under conditions similar to thealkylation of R¹R²CHCO₂R⁵ described above and subsequently reacted withdibromide 5 (for a discussion, see Larock, R. C. Comprehensive OrganicTransformations. A Guide to Functional Group Preparations, 2^(nd) ed.;Wiley-VCH, New York, 1999, pp 1717-1718). For example, a compound of theformula 5 (ortho, p=3, Hal=Br) is reacted with lithio ethyl isobutyrate(prepared from ethyl isobutyrate with lithium diisopropylamide) in asolvent mixture of THF and DMPU at a temperature ranging from about −78°C. to room temperature, affording the corresponding diester of formula 7(ortho, p=3). This diester is subsequently hydrolyzed under standardconditions (aqueous ethanol, potassium hydroxide, reflux temperature) toprovide, after re-acidification with dilute aqueous hydrochloric acid,the dicarboxylic acid of the formula 7 with ortho substitution pattern,R¹=R²=methyl and p=3. In another method, which is described in Gleiteret al, J. Org. Chem. 1992, 57, 252-258, isobutyric acid is deprotonatedtwice with n-butyl lithium and diisopropylamine in THF solution first atabout −20° C. and then at about 50° C. After re-cooling to about −20°C., a solution of a compound of the formula 5 (ortho, R¹=R²=methyl, p=3,Hal=Br) in THF is then added dropwise, while the temperature is keptbelow 10° C. The mixture is subsequently stirred first at roomtemperature and then at about 40° C., and worked up in a typical mannerto afford the corresponding diacid 7. Halide derivatives of type 5 canbe obtained by several methods, described for instance in Gleiter etal., J. Org. Chem. 1992, 57, 252-258.

In Scheme 4, Q¹ and Q² can each independently be —O-alkyl, —S-alkyl,—S-aryl, —NR^(1A)R^(2A), NHR^(1A), phenoxy, aryloxy, benzyl, aryl,cycloalkyl, F, Cl, Br, I, —CF₃, —COR^(1A), heteroaryl, or heterocyclyl,or each carbon atom together with the Q¹ and Q² attached to the carbonatom independently form a heterocyclyl or a carbocyclyl group. R^(1A)and R^(2A) are as defined herein for formula (I).

Scheme 4 illustrates the synthesis of para, meta, and orthodi-bromoalkyl substituted arene compounds 5-Br from the parentdicarboxylic acids 10 wherein (p−1) is an integer in the range from 1-2.Scheme 4 first outlines the esterification of compounds of the formula10 to diesters of the formula 20, wherein R is an alkyl moiety such as,but not limited to, methyl, ethyl, or isopropyl using general proceduresreferenced in Larock, R. C. Comprehensive Organic Transformations. AGuide to Functional Group Preparations, 2^(nd) ed.; Wiley-VCH, New York,1999, pp 1932-1941 and Smith, M. B.; March, J. March's Advanced OrganicChemistry. Reactions, Mechanisms, and Structure, 5^(th) ed.; John Wileyand Sons, New York, 2001, pp 484-486. Diols 30 can be prepared fromdiesters 20 by well-known synthetic methods (for a discussion ofsuitable reduction methods, see for example Hudlicky, M. Reductions inOrganic Chemistry, 2^(nd) ed.; ACS Monograph 188, Washington, D C, 1996,pp 212-216). In the next step, transformation of the alcoholfunctionalities in 30 to the bromo moieties in Compound 5-Br can beaccomplished by a variety of standard methods as referenced in Larock,R. C. Comprehensive Organic Transformations. A Guide to Functional GroupPreparations, 2^(nd) ed.; Wiley-VCH, New York, 1999, pp 693-695. Forexample, a compound of the formula 10 with para substitution pattern and(p−1)=1 (available from Aldrich Chemical Co., Milwaukee, Wis.) istreated with an excess of methanol and concentrated sulfuric acid atreflux temperature to give the corresponding dimethyl ester of theformula 2. A procedure that can be used for this transformation is, forexample, referenced in Schimelpfenig, C. W. J. Org. Chem. 1975, 40,1493-1494, incorporated by reference herein. In addition, a compound ofthe formula 20 (para, (p−1)=1) can be transformed to the correspondingcompound of the formula 30 by reaction with a complex metal hydride,preferably, but not limited to, lithium aluminum hydride in an aproticorganic solvent, such as THF or diethyl ether, as referenced in Reynoldset al. U.S. Pat. No. 2,789,970, Appl. No. 397,037, filed Dec. 8, 1953.Further, a diol of the formula 30 (para, p=1) can be converted to abromide of the formula 5-Br (para, p=1) by treatment with sodium bromideand concentrated sulfuric acid at elevated temperature. A useful solventfor this conversion is water, as is described in Schimelpfenig, C. W. J.Org. Chem. 1975, 40, 1493-1494.

In Scheme 5, Q¹ and Q² can each independently be —O-alkyl, —S-alkyl,—S-aryl, —NR^(1A)R^(2A), NHR^(1A), phenoxy, aryloxy, benzyl, aryl,cycloalkyl, F, Cl, Br, I, —CF₃, —COR^(1A), heteroaryl, or heterocyclyl,or each carbon atom together with the Q¹ and Q² attached to the carbonatom independently form a heterocyclyl or a carbocyclyl group. R^(1A)and R^(2A) are as defined herein for formula (I).

Scheme 5 illustrates the preparation of ortho, meta, and parasubstituted arene compounds with two 3-bromopropyl substituents of theformula 5A-Br. Specific examples for the synthesis of compounds 5A-Brwith meta and para substitution are given in Schimelpfenig, C. W. J.Org. Chem. 1975, 40, 1493-1494 and Gleiter et al, J. Org. Chem. 1992,57, 252-258, respectively. For example, a compound of the formula 50 istreated with malonic acid and piperidine in pyridine solution at about90-110° C. to give an α,β-unsaturated carboxylic acid of the formula 60.The end point of this conversion is typically indicated by cessation ofthe CO₂ effervescence. This procedure is known as a Knoevenagel-Doebnerreaction and a useful reaction protocol for this conversion is given inOrganikum, Organisch-Chemisches Grundpraktikum, VEB Verlag DeutscherWissenschaften, Berlin 1984, pp 572-574. Reduction of compounds of theformula 60 to compounds of the formula 70 can be accomplished bycatalytic hydrogenation over colloidal palladium, Raney nickel, orcopper chromite as discussed in Hudlicky, M. Reductions in OrganicChemistry, 2^(nd) ed.; ACS Monograph 188, Washington, D C, 1996, pp196-197. Conversion of a compound of the formula 60 with metasubstitution to the corresponding compound 70 by treatment with hydrogengas at pressures from ca. 20-60 psi and palladium on carbon catalyst inaqueous sodium hydroxide solution is reported in Schimelpfenig, C. W. J.Org. Chem. 1975, 40, 1493-1494, which is included herein as a referencein its entirety. The further transformation of compounds of the formula70 to compounds of formula 5A-Br can then be accomplished according tothe methodology described in Scheme 4.

In Scheme 6, Q¹ and Q² can each independently be —O-alkyl, —S-alkyl,—S-aryl, —NR^(1A)R^(2A), NHR^(1A), phenoxy, aryloxy, benzyl, aryl,cycloalkyl, F, Cl, Br, I, —CF₃, —COR^(1A), heteroaryl, or heterocyclyl,or each carbon atom together with the Q¹ and Q² attached to the carbonatom independently form a heterocyclyl or a carbocyclyl group. R^(1A)and R^(2A) are as defined herein for formula (I).

Scheme 6 illustrates a general method for the chain elongation ofbromides of the formula 90 with an alkyl chain consisting of (p−2)methylene groups to bromides of the formula 5-Br with an alkyl chainconsisting of p methylene groups. The conversion sequence from alkylhalides (such as 90) to carboxylic acid (such as 120) can beaccomplished using a malonic ester synthesis referenced in Smith, M. B.;March, J. March's Advanced Organic Chemistry. Reactions, Mechanisms, andStructure, 5^(th) ed.; John Wiley and Sons, New York, 2001, p 549 andLarock, R. C. Comprehensive Organic Transformations. A Guide toFunctional Group Preparations, 2^(nd) ed.; Wiley-VCH, New York, 1999, p1765. Generally, the monoalkylation of malonic esters (R is typicallyethyl or methyl) employs the base-solvent combination of sodium ethoxidein ethanol, which inhibits the formation of dialkylated side-products(Organic Reactions, Volume IX, editor-in-chief: R. Adams; Robert E.Krieger Publishing Company, Malabar, Fla., 1957, p 132) to givecompounds of the formula 100. Compounds of the formula 100 are thensaponified to give compounds of the formula 110, which can be heatedabove their melting point for decarboxylation to compounds of theformula 120. The transformation from dicarboxylic acids 120 via diesters20 to the chain-elongated dibromides 5-Br is then conducted according tothe methodologies described in Scheme 4. Alternatively, a directdecarbalkoxylation of geminal diesters 100 to compounds of the formula20 can be achieved by treatment with water and DMSO with or without thepresence of added salts. However, the addition of salts such as KCN,NaCl or LiCl to the water/DMSO solvent can enhance thedecarbalkoxylation rates of theses substrates (Fakhri, S. A.; Yousefi,B. H. Tetrahedron 2000, 56, 8301-8308). For example, ethyl malonate isreacted with sodium metal in ethanol and a solution of a compound of theformula 90 with (p−2)=2, and ethyl malonate is added to give thecorresponding compound of the formula 100. This tetraester issubsequently saponified using, for example, aqueous ethanol andpotassium hydroxide, yielding the corresponding tetraacid of the formula110. The tetraacid is then decarboxylated at a temperature of ca. 200°C. to the diacid of the formula 120. After esterification with methanoland concentrated sulfuric acid (see Scheme 4) to diester 20. Usefulmethods for the transformation of a tetraester of the formula 100(ortho, (p−2)=1, R=ethyl) to a diester of the formula 20 are describedin Fakhri, S. A.; Yousefi, B. H. Tetrahedron 2000, 56, 8301-8308, whichis included herein in its entirety as a reference.

In Scheme 7, Q¹ and Q² can each independently be —O-alkyl, —S-alkyl,—S-aryl, —NR^(1A)R^(2A), NHR^(1A), phenoxy, aryloxy, benzyl, aryl,cycloalkyl, F, Cl, Br, I, —CF₃, —COR^(1A), heteroaryl, or heterocyclyl,or each carbon atom together with the Q¹ and Q² attached to the carbonatom independently form a heterocyclyl or a carbocyclyl group. R^(1A)and R^(2A) are as defined herein for formula (I).

Scheme 7 illustrates the synthesis of ortho, meta, and para substitutedarene compounds of the formula 7 with co-carboxyalkyl substitution,wherein (p−1) is an integer in the range from 2-12 and R¹ and R² areeither alkyl and/or aryl moieties or two alkyl moieties connected in a3- to 7-membered cycle. The synthesis starts with the twofolddeprotonation of ortho-, meta-, or para-xylene 3 with a strong base,such as, but not limited to, a combination of n-butyl lithium andpotassium tert-butoxide in an aprotic solvent, such as, but not limitedto, hexane and reaction of the formed dianion of 3 with suitableelectrophiles A-(CH₂)_(p−1)—CR¹R²—CH₂O—PG, wherein (p−1), R¹, and R² aredefined as above and A is Cl, Br, or I. “PG” is a hydroxyl-protectinggroup. Examples of hydroxyl-protecting groups are described in Greene,T. W.; Wuts, P. G. M. Protective groups in organic synthesis, 3^(rd)ed., John Wiley and Sons, New York, 1999, pp 17-245, which isincorporated herein by reference. Methyl arenes can be alkylated viadeprotonation using lithium bases followed by alkylation with suitableelectrophiles according to Larock, R. C. Comprehensive OrganicTransformations. A Guide to Functional Group Preparations, 2^(nd) ed.;Wiley-VCH, New York, 1999, p 88. See, Bates et al, J. Am. Chem. Soc.1981, I03, 5052-5058, for an example for the preparation of xylenedianions. In the following step, the protective groups of 190 areremoved to liberate the terminal hydroxylmethyl moieties in 200, whichare the oxidized using a suitable oxidizing agent (Larock, R. C.Comprehensive Organic Transformations. A Guide to Functional GroupPreparations, 2^(nd) ed.; Wiley-VCH, New York, 1999, pp 1646-1648 andSmith, M. B.; March, J. March's Advanced Organic Chemistry. Reactions,Mechanisms, and Structure, 5^(th) ed.; John Wiley and Sons, New York,2001, p 1537) to give a dicarboxylic acid of the formula 7. For example,m-xylene (meta-3) is reacted with n-butyl lithium and potassiumtert-butoxide in hexanes, first at room temperature and then at refluxtemperature. After cooling to 0° C., a compound of the formula 180(A=Br, (p−1)=3, R¹=R²=methyl, PG=tetrahydropyranyl, prepared accordingto Dasseux et al, U.S. Pat. Nos. 6,646,170 and 6,410,802) is added andreaction is continued at reflux temperature, affording, after the usualworkup and purification by column chromatography, the correspondingcompound of the formula 190. Deprotection of 190 to 200 (R¹, R²=methyl,p=3) is then accomplished by heating in methanol and concentrated,aqueous hydrochloric acid (Vogel, A. I. Vogel's textbook of practicalorganic chemistry, 5^(th) ed., Longman Scientific and Technical, 1989,p. 552). This compound 200 is then treated with pyridinium dichromate inN,N-dimethylformamide according to Vedejs, E.; Dent, W. H., III;Gapinski, D. M.; McClure, C. K. J. Am. Chem. Soc. 1987, 109, 5437-5446to yield the dicarboxylic acid of the formula 7 (meta, p=3;R¹,R²=methyl).

Scheme 8 shows illustrative alternate syntheses of compounds 1-1 and1-32. Commercially available benzene-dicarboxaldehydes (Sigma-Aldrich,AK Scientific, etc.) are reacted with(5-ethoxy-4,4-dimethyl-5-oxopentyl)triphenylphosphonium bromide (220)(prepared as described in Oniciu, D, C. et al., WO2012/054535 and U.S.Pat. No. 8,349,833 B2) in the presence of base (including but notlimited to sodium or potassium hydroxide, potassium or sodiumtert-butoxide, potassium or sodium carbonate, and sodium hydride), inthe manner described in Le Bigot Y. et al., 1988, Tetrahedron 44(4), pp.1057-1072, as a mixture of cis and trans isomers. The mixture of cis andtrans isomers of formula (230) or (240) can be reduced catalytically bymethods for the hydrogenation of olefins known in the art, such as themethods described by H.-U. Blaser, F. Spindler, M. Thommen, The Handbookof Homogeneous Hydrogenation, J. G. De Vries, C. J. Elsevier, Eds.(Wiley-VCH, 2008), chap. 37; Schamagl, F. K. et al., Sci. Adv. 2018; 4:eaaul248, 21 Sep. 2018; and references cited herein. The esters thusobtained are subjected to hydrolysis after the hydrogenation reaction isdeemed substantially complete by using an appropriate analyticalmethods. The reaction mixtures containing compounds of formula (250) or(260), respectively, are hydrolyzed in the presence of an alkaline earthmetal salt or base, or oxide, or alkali metal salt or base, in refluxingalcohols for 2 to 96 hours. Typical examples include, but are notlimited to, hydrolysis with K₂CO₃ in a refluxing mixture of DMSO andwater. Other suitable procedures are referenced in Houben-Weyl, Methodender Organische Chemie, Georg Thieme Verlag Stuttgart 1964, vol. XIE2,pp. 143-210 and 872-879, or Anderson, N. G., Practical Process Research& Development, Academic Press, London, 2000, pp. 93-94 and 181-182.

The compound of Formula (III) or (IIIA) where X=O can be prepared by aWilliamson synthesis, by reacting an alcohol with a derivativecomprising a leaving group such as halide, tolylsulphonate or mesylate.See Scheme 9.

SYNTHESIS EXAMPLES Example 1: Synthesis of(9-Carboxymethylsulfanyl-5-oxo-nonylsulfanyl)-acetic Acid (CompoundII-3)

Reaction of ethyl 5-bromovalerate with lithium diisopropylamide in THFat room temperature produces ketone ester 1-1 (see, e.g., Cooke, M. P.J. Org. Chem. 1993, 58, 2910-2912; Stetter, H.; Rauhut, H. Chem. Ber.1958, 91). Decarboxylation of 1-1 by refluxing in HCl/EtOH (Cooke, M. P.J. Org. Chem. 1993, 58, 2910-2912) produces crude 1-2, which can bepurified by column chromatography using systems such as silica gel andmixtures of ethyl acetate/hexanes in ratios from 1/20 to 1/8.Mercaptoacetic acid dissolved in mixtures of ethanol and water istreated with a solution of sodium hydroxide in water to make sodiummercaptoacetate and is used to treat 1-2 in solvents such as ethanol asdescribed in Agnus, A., Louis, Gissebrecht, J. P., Weiss, R., J. Am.Chem. Soc., 1984, 106, 93 or Riesen, P. C.; Kaden, T. A. Helv. Chim.Acta. 1995, 78, 1325-1333, to provide crude compound II-3. The crudecompound II-3 can be purified by recrystallization from solvents ormixtures of solvents such as MTBE and heptane.

Example 2: Synthesis of(9-Carboxymethylsulfanyl-5-hydroxy-nonylsulfanyl)-acetic Acid (CompoundII-1)

The reduction of ketodiacid compound II-3 from Example 1 is achievedwith sodium borohydride after salt formation with NaOH to yield compoundII-1 (see U.S. Pat. No. 7,119,221 for suitable reaction conditions).Compound II-3 (Example 1) is dissolved in NaOH solution (2 to 7 equiv)to form an intermediate disodium salt in water. Isopropanol is thenadded followed by addition of sodium borohydride (1.05 equiv) inportions. The reaction mixture is heated at about 45° C. for a few hoursto yield compound II-1. Such product can be purified byrecrystallization from MTBE, heptane or mixtures.

Example 3: Synthesis of[5-(5-Carboxymethoxy-pentyloxy)-pentyloxy]-acetic Acid (Compound II-12)

Compound II-12 is prepared via a Williamson ether synthesis startingfrom 3-1 and 3-2 (prepared as described in Dasseux et al. U.S. Pat. No.6,459,003). The resulting 3-3 is deprotected in methanol in the presenceof a catalytic amount of tert-toluenesulphonic acid monohydrate to givediol 3-4. This diol is then coupled with tert-butyl bromoacetate in atwo-phase system of aqueous NaOH and toluene in the presence oftetrabutylammonium bromide as PTC catalyst, as described in U.S. Pat.No. 10,227,285. Finally, this tert-butyl ester is cleaved under acidicconditions to afford compound 11-12.

Example 4: Synthesis of[5-(5-Carboxymethoxy-pentylsulfanyl)-pentyloxy]-acetic Acid (CompoundII-20)

Compound 3-1 (prepared as described in U.S. Pat. No. 6,790,953) istreated with sodium sulfide similarly to the method by Edwards, D.;Stenlake, J. B. J. Pharmacy Pharmacol. 1955, 7, 852-860, to form thioether 4-1, which is deprotected in methanol in the presence of acatalytic amount of pyridinium p-toluenesulphonate (PPTS) as describedin Miyashita, N.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem. 1977,42(23), 3772-73. The diol 4-2 thus obtained is reacted with tert-butylbromoacetate under phase-transfer catalysis conditions using(Bu₄N)(HSO₄) as catalyst, following the method of Nagatsugi, F.; Sasaki,S.; Maeda, M. J. Fluorine Chem. 1992, 56, 373-383, to obtain itstert-butyl ester 4-3. Subsequent cleavage of tert-butyl ester bytrifluoroacetic acid (TFA) affords free acid compound 11-20 in 90% yieldsimilar to the procedure in Nagatsugi, F.; Sasaki, S.; Maeda, M. J.Fluorine Chem. 1992, 56, 373-383.

Example 5: Synthesis of[5-(5-Carboxymethoxy-pentane-1-sulfinyl)-pentyloxy]-acetic Acid(Compound II-24)

Compound II-24 is prepared starting from compound 11-12 (Example 4)using hydrogen peroxide as an oxidizer similarly to the proceduredescribed in U.S. Pat. No. 6,673,780.

Example 6: Synthesis of[5-(5-Carboxymethylsulfanyl-pentyloxy)-pentylsulfanyl]-acetic Acid(Compound II-6)

Compounds 6-1 and 6-2 are obtained according the methods described inHarrison, G. C.; Diehl, H. Organic Synthesis 1955 Coll. Vol 3, 370, andFrancis, G. W.; Berg, J. F. Acta Chem. Scand. B 1977, 31, 721-722,respectively. 5-Chloro-pentan-1-ol is commercially available and 3-4 isprepared as described in Example 3, as follows: mercaptoacetic acid (8.1g, 87.9 mmol) was dissolved in deionized water/ethanol solution (50mL/40 mL). A solution of sodium hydroxide (7.0 g, 175.5 mmol) in water(50 mL) was added under stirring. To this mixture, bis(4-chlorobutylether) (7.0 g, 35.1 mmol) in ethanol (20 mL) was added dropwise over 30min. This mixture was heated to reflux for 20 h, with subsequentevaporation of ethanol. The residue was diluted with water (20 mL). Theaqueous layer was extracted with MTBE (4×20 mL) and the organic layerswere discarded. The aqueous layer was acidified with coned HCl to pH 2(ca. 12 mL) and extracted with MTBE (4×30 mL). The combined organiclayers were checked by TLC (silica, CH2Cl2:MeOH=9:1) for presence ofstarting mercaptoacetic acid (R_(f)=0.7; bright blue spot withphosphomolybdic acid/EtOH). The organic layer was washed with wateruntil the starting acid was completely gone (ca. 700 mL in portions).The solvent was removed under reduced pressure to give a colorless oil(7.7 g), which solidified at rt. This solid was recrystallized fromheptane/MTBE (50/60 mL) to give nice white crystals (6.2 g, yield 57%;purity 99%—RI, 91%—UV, mp 43-44° C.). An additional amount of theproduct was obtained from the mother liquor (0.87 g, mp 38-40° C.).

Example 7: Synthesis of(11-Carboxymethylsulfanyl-6-oxo-undecylsulfanyl)-acetic Acid (CompoundII-4) and (11-Carboxymethylsulfanyl-6-hydroxy-undecylsulfanyl)-aceticAcid (Compound II-2)

The synthesis of compounds II-4 and II-2 begins with1,11-dibromoundecan-6-one (7-4), prepared as shown in above, startingwith commercially available 6-bromohexanol. Protection of6-bromohexanol's hydroxyl group with dihydropyran affords intermediate7-1 as described in U.S. Pat. Nos. 6,646,170 and 6,410,802. Reaction of7-1 with TosMIC in dimethyl acetamide (DMAc) in the presence of sodiumamylate (NaOAm-t) leads to formation of intermediate 7-2, which istransformed to diol 7-3. The removal of the THP-protective groups andthe transformation of the isocyano-tosyl-fragment into the ketone groupproceeds simultaneously in mixture of solvents, such as methylenechloride, methanol, in the presence of aqueous HCl in about 12 to 24hours. Diol 7-3 may be purified by column chromatography on silica geland mixtures of solvents, such as ethyl acetate and methylene chloride.Compound 7-3 thus obtained is subjected to a Mitsunobu reaction toafford bromide 7-4, which is subsequently treated with the sodium saltof mercaptoacetic acid in an alcohol or a mixture of alcohols (ethanol,isopropanol) to provide diacid compound II-4. Compound II-4 is reducedwith sodium borohydride to provide compound II-2 (see Example 2).

Example 8: Synthesis of [4-(4-Carboxymethoxy-butoxy)-butoxy]-acetic Acid(Compound II-11)

Commercially available bis(4-chlorobutyl ether) is converted viadiacetate 8-1 [Kliem, A., Schniepp, L. E. J. Am. Chem. Soc, 1948, 70,1839] to diol 8-2, which is further reacted with ethyl bromoacetate toprovide 8-3. Compound 8-3 is hydrolyzed to provide II-11. Alternatively,bis(4-chlorobutyl ether) is treated with the dianion of hydroxyaceticacid to provide compound 11-11 via autoclave or high temperatures.

Specifically, diacetate 8-1 is treated with potassium carbonate inmethanol similarly to the method described in Kliem, A., Schniepp, L. E.J. Am. Chem. Soc, 1948, 70, 1839, and the crude compound 8-2 isoptionally purified by column chromatography. Diol 8-2 is reacteddeprotonated with sodium hydride (95% or 60% in mineral oil) in THF forabout 2 h to about 4 h and then it is reacted with ethyl bromoacetate togive diester 8-3. The last step, hydrolysis of 8-3, is carried out withKOH in ethyl alcohol for about 2 to about 8 h. The product is thensubjected to workup, including acidification with aqueous HCl followedby extraction with methylene chloride, to provide crude compound 11-11.Crude compound 11-11 is optionally purified by gradient columnchromatography on silica gel using solvents such as EtOAc and hexanesand their mixtures.

Example 9: Synthesis of 5,5′-(1,4-Phenylene)bis(2,2-dimethylpentanoicAcid) (Compound I-78)

(4-Methoxycarbonylmethylphenyl)-acetic Acid Methyl Ester (A2)

Concentrated sulfuric acid (40 mL) was added to phenylenediacetic acid(A1) (25.0 g, 0.129 mol) in MeOH (300 mL). The reaction mixture washeated to reflux overnight. Most of the MeOH was evaporated in vacuum.The residue was diluted with EtOAc (300 mL) and water (300 mL). Theaqueous solution was separated and extracted with EtOAc (2×100 mL). Thecombined organic solutions were washed with water (100 mL), saturatedNaHCO₃ solution (2×100 mL) and brine (100 mL), and dried over MgSO₄. Thesolvent was evaporated to yield (4-methoxycarbonylmethylphenyl)-aceticacid methyl ester (27.1 g, 95%, 92.3% by HPLC) as a white solid. Mp59-60° C. (51-54° C., Dynamit Nobel, British patent 1495472, Appl. No.9008/75, filed Mar. 4, 1975). ¹H NMR (CDCl₃): δ=7.25 (s, 4H), 3.70 (s,6H), 3.60 (s, 4H). ¹³C NMR (CDCl₃): δ=174.0, 132.5, 129.0, 52.0, 40.5.

2-[4-(2-Hydroxyethyl)-phenyl]-ethanol (A3)

(4-Methoxycarbonylmethylphenyl)-acetic acid methyl ester (A2) (26.5 g,0.12 mol) in THF (100 mL) was added to a solution of LiAlH₄ (11.0 g,0.29 mol) in THF (300 mL) at room temperature with stirring. Thereaction mixture was heated to reflux for 2 h. Water (100 mL) wascarefully added followed by addition of dilute, aqueous HCl (75 mL conedHCl in 100 mL of water). The aqueous phase was extracted with EtOAc(2×100 mL). The combined organic solutions were washed with water (100mL), saturated NaHCO₃ solution (150 mL) and brine (100 mL), and driedover MgSO₄. The solvent was evaporated to yield2-[4-(2-hydroxyethyl)-phenyl]-ethanol (18.68 g, 94%, 93.5% pure by HPLC)as a white solid. Mp 89-90° C. (87-88° C., Reynolds et al. U.S. Pat. No.2,789,970, Appl. No. 397,037, filed Dec. 8, 1953). ¹H NMR (CDCl₃):δ=7.17 (s, 4H), 3.78 (t, J=6.6 Hz, 4H), 2.81 (t, J=6.6 Hz, 4H), 2.30 (brs, 2H). ¹³C NMR (CDCl₃): δ=136.9, 129.4, 63.8, 39.0.

1,4-Bis-(2-bromoethyl)-benzene (A4)

Concentrated sulfuric acid (30.0 g) was added dropwise over 1 h into aboiling mixture of 2-[4-(2-hydroxyethyl)-phenyl]-ethanol (A3) (18.29 g,0.11 mol), NaBr (40.0 g, 0.39 mol) and water (50 mL). The reactionmixture was heated to reflux for 1 h. Additional portions of sulfuricacid (10 mL) and NaBr (16.0 g, 0.16 mol) were added and heating atreflux was continued for 1.5 h. Water (100 mL) was added to the cooledmixture and the product was extracted with methylene chloride (3×100mL). The combined organic solutions were washed with water (100 mL) andbrine (100 mL), and dried over MgSO₄. The solvent was evaporated and theresidue was purified by column chromatography (silica gel,EtOAc:hexanes, 1:1). The solid product was recrystallized from hexanesto yield 1,4-bis-(2-bromoethyl)-benzene (22.27 g, 69%, 99.8% pure byHPLC) as a white solid. Mp 71-72° C. (70-71° C., Longone, D. T.;Kiisefoglu, S. H.; Gladysz, J. A. J. Org. Chem. 1977, 42, 2787-2788. ¹HNMR (CDCl₃): δ=7.18 (s, 4H), 3.57 (t, J=2.2 Hz, 4H), 3.16 (t, J=7.8 Hz,4H). ¹³C NMR (CDCl₃): δ=138.6, 130.0, 40.1, 34.0.

4-[4-(3-Carboxy-3-methylbutyl)-phenyl]-2,2-dimethylbutyric Acid

A solution of lithium diisopropyl amide (89 mL, 0.16 mol, 1.8 M inheptane/THF/EtPh) was added dropwise to a solution of ethyl isobutyrate(18.0 g, 155 mmol) in THF (100 mL) at −78° C. The reaction mixture wasstirred for 1 h and a solution of 1,4-bis-(2-bromoethyl)-benzene (A4)(20.0 g, 68.5 mmol) in THF (50 mL) was added slowly followed by DMPU (10mL). The reaction mixture was warmed to room temperature over 2 h andstirred for 1 h at 40-50° C. Water (200 mL) was added, the aqueoussolution was separated, and extracted with EtOAc (3×80 mL). The combinedorganic solutions were washed with water (100 mL) and brine (100 mL).After concentration under reduced pressure, the residue was purified bycolumn chromatography (silica gel, EtOAc:heptane, 1:10) to give4-[4-(3-ethoxycarbonyl-3-methylbutyl)-phenyl]-2,2-dimethylbutyric acidethyl ester (24.0 g). This intermediate (24.0 g, 66.2 mmol) wasdissolved in EtOH (300 mL) and water (50 mL), KOH (85%, 15.0 g, 227mmol) was added, and the reaction mixture was refluxed for 3 h. Thesolvent was evaporated, the residue was dissolved in water (150 mL) andextracted with MTBE (2×30 mL). The aqueous solution was acidified withaqueous HCl to pH 1-2. The precipitate was filtered, recrystallized fromCHCl₃/EtOH (1:1), and dried in vacuum to give4-[4-(3-carboxy-3-methylbutyl)-phenyl]-2,2-dimethylbutyric acid (13.6 g,64%, 94.8% pure by HPLC) as white crystals (Compound I-78). Mp 214-215°C. Elemental analysis (C₁₈H₂₆O₄): Calcd for C, 70.56; H, 8.55. found: C,70.78; H, 8.64. ¹H NMR (CD₃OD): δ=7.06 (s, 4H), 4.90 (s, 2H), 2.54-2.48(m, 4H), 1.80-1.74 (m, 4H), 1.22 (m, 12H). ¹³C NMR (CD₃OD): δ=181.5,140.9, 129.2, 44.3, 43.2, 32.3, 25.8. HRMS calcd for C₁₈H₂₆O₄ (M⁺):306.1831. found: 306.1831.

Example 10: Synthesis of 6,6′-(1,4-phenylene)bis(2,2-dimethylhexanoicAcid) (Compound I-1)

4-[4-(3-Methoxycarbonylpropyl)-phenyl]-butyric Acid Methyl Ester (B1)

The compound was prepared by a modified method than reported in Cram, D.J.; Allinger, N. L.; Steinberg, H. J. Amer. Chem. Soc. 1954, 76, 6132.

Under N₂ atmosphere, sodium (3.5 g, 0.152 mol) was dissolved in EtOH(200 mL) and ethyl malonate (50.0 g, 0.31 mol) was added to the warmsolution. The reaction mixture was heated to reflux for 5 min and asolution of 1,4-bis-(2-bromoethyl)-benzene (A4) (22.02 g, 75.4 mmol) inethyl malonate (50 mL) was added dropwise at the room temperature over 5min. The reaction mixture was heated to reflux for 0.5 h. After theaddition of water (150 mL) and EtOAc (200 mL), the solvents wereevaporated, and the residue was dissolved in EtOAc (200 mL). Thesolution was washed with water (100 mL) and brine (100 mL), dried overMgSO₄, and concentrated in vacuo. The residue was dried in high vacuumat 80-100° C. (oil bath). The obtained crude2-{2-[4-(3,3-bis-ethoxycarbonylpropyl)-phenyl]-ethyl}malonic aciddiethyl ester was dissolved in aqueous EtOH (80%, 200 mL) and KOH (85%,35.0 g, 0.53 mol) was added. The reaction mixture was heated to refluxfor 2 h. The solvent was partially evaporated and EtOAc (150 mL) wasadded. The aqueous layer was separated and extracted with EtOAc (2×100mL). The combined organic solutions were washed with brine (100 mL),dried over MgSO₄, and concentrated. The crude2-{2-[4-(3,3-bis-carboxypropyl)-phenyl]-ethyl}malonic acid (28.0 g) washeated on an oil bath at 200-210° C. for 1.5 h. The obtained, crude4-[4-(3-carboxypropyl)-phenyl]-butyric acid (16.3 g) was dissolved inMeOH (100 mL) and concentrated sulfuric acid (40 mL) was added. Thereaction mixture was refluxed for 5 h, then stirred overnight at roomtemperature. The MeOH was partially evaporated, the residue wasdissolved in EtOAc (150 mL), washed with water (150 mL) and brine (150mL), and dried over MgSO₄. The solvent was evaporated to yield crude4-[4-(3-methoxycarbonylpropyl)-phenyl]-butyric acid methyl ester (B1)(17.9 g, 85%) as a yellow oil, which was used without purification forthe next step. ¹H NMR (CDCl₃): δ=7.10 (s, 4H), 3.67 (s, 6H), 2.59 (t,J=7.4 Hz, 4H), 2.33 (t, J=7.4 Hz, 4H), 1.95-1.90 (m, 4H). ¹³C NMR(CDCl₃): δ=174.0, 138.9, 128.4, 51.5, 34.6, 33.3, 26.5.

4-[4-(4-Hydroxybutyl)-phenyl]-butan-1-ol (B2)

The compound is prepared according to Cram, D. J.; Allinger, N. L.;Steinberg, H. J. Am. Chem. Soc. 1954, 76, 6132-6141). A solution of4-[4-(3-methoxycarbonylpropyl)-phenyl]-butyric acid methyl ester (17.7g, 63.6 mmol) in THF (50 mL) was added to a suspension of LiAlH₄ (7.2 g,0.19 mol) in THF (300 mL) with stirring at 0° C. The reaction mixturewas heated to reflux for 1 h. Water (100 mL) and aqueous HCl (10%, 200mL) were added. The aqueous layer was separated and extracted with EtOAc(2×50 mL). The combined organic solutions were washed with brine, driedover MgSO₄, and concentrated. The residue was purified by columnchromatography (silica gel, ETOAc:hexanes, 1:1) to yield4-[4-(4-hydroxybutyl)-phenyl]-butan-1-ol (7.5 g, 53%, 96.2% pure byHPLC) as white crystals. Mp 60-62° C. (60.5-62.4° C., Cram, D. J.;Allinger, N. L.; Steinberg, H. J. Am. Chem. Soc. 1954, 76, 6132-6141).¹H NMR (CDCl₃): δ=7.10 (s, 4H), 3.63 (t, J=6.4 Hz, 4H), 2.61 (t, J=7.1Hz, 4H), 2.12 (br s, 2H), 1.71-1.57 (m, 8H). ¹³C NMR (CDCl₃): δ=140.7,129.4, 63.8, 36.3, 33.4, 28.67.

1,4-Bis-(4-bromobutyl)-benzene (B3)

Concentrated sulfuric acid (30 mL) was added dropwise to a boilingmixture of 4-[4-(4-hydroxybutyl)-phenyl]-butan-1-ol (9.4 g, 42.3 mmol),NaBr (17.4 g, 0.169 mol) and water (50 mL) over 1 h. The reactionmixture was refluxed for 1 h. Additional concentrated sulfuric acid (10mL) was added over 20 min and refluxing was continued for 1.5 h. Afterthe addition of water (300 mL) and methylene chloride (500 mL), theaqueous solution was separated and extracted with methylene chloride(2×50 mL). The combined organic solutions were washed with water (200mL) and brine (150 mL), and dried over MgSO₄. The solvent was evaporatedand residue was purified by column chromatography (silica gel,EtOAc:hexanes, 1:20) to yield 1,4-bis-(4-bromobutyl)-benzene (11.8 g,80%, 96.1% pure by HPLC) as an oil. ¹H NMR (CDCl₃): δ=7.14 (s, 4H), 3.46(t, J=6.6 Hz, 4H), 2.65 (t, J=7.5 Hz, 4H), 1.96-1.89 (m, 4H), 1.83-1.75(m, 4H). ¹³C NMR (CDCl₃): δ=139.5, 128.6, 34.7, 34.0, 32.5, 30.1. Thisprocedure is modified from the one described by Cram, D. J.; Allinger,N. L.; Steinberg, H. J. Am. Chem. Soc. 1954, 76, 6132-6141.

6-[4-(5-Carboxy-5methylhexyl)-phenyl]-2,2-dimethylhexanoic Acid

A solution of lithium diisopropyl amide (90 mmol, 1.8 M inheptane/THF/EtPh, 50 mL) was added dropwise to a solution of ethylisobutyrate (8.97 g, 77.2 mmol) in THF (200 mL) at −78° C. The reactionmixture was stirred for 1 h before a solution of1,4-bis-(4-bromobutyl)-benzene (11.2 g, 32.2 mmol) in THF (50 mL) wasadded slowly, followed by addition of DMPU (10 mL). The reaction mixturewas warmed to room temperature over 2 h and stirred for 1 h at 40-50° C.Water (200 mL) was added, the aqueous solution was separated, andextracted with EtOAc (3×80 mL). The combined organic solutions werewashed with water (100 mL) and brine (100 mL). The solvent wasevaporated, and the residue was dissolved in EtOH (100 mL). Water (50mL) and KOH (85%, 15.0 g, 227 mmol) were added and the reaction mixturewas heated to reflux for 3 h. After addition of water (200 mL) andcooling to room temperature, the reaction mixture was acidified withconcentrated HCl to pH 1 and stirred for 1 h. The precipitate wasfiltered, washed with water and dissolved in methylene chloride (400mL). The solution was dried with MgSO₄ and evaporated in vacuum. Theresidue was dissolved under heating in EtOAc:hexanes (1:30, 200 mL) andcooled in a freezer. The solution was decanted from the oil andevaporated to a volume of 60 mL. The mixture was stirred overnight, theprecipitate was filtered, washed with hexanes, and dried in vacuum toyield 6-[4-(5-carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoic acid(8.02 g, 69%, 96.4% pure by HPLC) as a white solid (Compound I-1). Mp129-131° C. Elemental analysis (C₂₂H₃₄O₄): Calcd for C, 72.89; H, 9.45.Found: C, 72.90; H, 9.49. ³H NMR (CDCl₃): δ=7.05 (s, 4H), 2.66-2.62 (m,4H), 1.68-1.56 (m, 4H), 1.53-1.47 (m, 4H), 1.17 (s, 12H), 1.08-0.98 (m,4H). ¹³C NMR (CDCl₃): δ=185.3, 138.6, 128.5, 42.3, 41.5, 34.5, 30.6,25.0, 23.2. HRMS calcd for C₂₂H₃₄O₄ (M⁺): 362.2457. found: 362.2453.

Example 11: Synthesis of 1,4-Bis(4-carboxy-4-methylpentyl)benzene(Compound III-1)

1,4-Bis(2-methoxycarbonylethyl)benzene (C2)

Under Ar-atmosphere, a solution of 1,4-bis(2-carboxyethyl)benzene (C1)(10.0 g, 45.0 mmol) in anhydrous methanol (75 mL) and concentratedsulfuric acid (5.0 g) was heated to reflux for 5 h. The reaction mixturewas cooled to room temperature, the crystals were filtered, washed withMeOH (30 mL), and dried in vacuum to yield1,4-bis(2-methoxycarbonylethyl)-benzene (11.0 g, 99%) as white crystals.Mp 116-117° C. (116-118° C., Matsuoka, T.; Negi, T.; Otsubo, T.; Sakata,Y.; Misumi, S. Bull. Chem. Soc. Japan 1972, 45, 1825-1833). ¹H NMR(CDCl₃): δ=7.11 (s, 4H), 3.69 (s, 6H), 2.94 (t, J=8.1 Hz, 4H), 2.62 (t,J=8.2 Hz, 4H). ¹³C NMR (CDCl₃): δ=173.3, 138.4, 128.4, 51.6, 35.6, 30.5.This known compound was prepared by a method different from the onedescribed in Matsuoka, T.; Negi, T.; Otsubo, T.; Sakata, Y.; Misumi, S.Bull. Chem. Soc. Japan 1972, 45, 1825-1833.

1,4-Bis(3-hydroxypropyl)benzene (C3)

C3 was prepared according to Matsuoka, T.; Negi, T.; Otsubo, T.; Sakata,Y.; Misumi, S. Bull. Chem. Soc. Japan 1972, 45, 1825-1833. UnderAr-atmosphere, lithium aluminum hydride (5.2 g, 13.7 mmol) was added inportions to anhydrous THF (300 mL). A solution of1,4-bis(2-methoxycarbonylethyl)benzene (11.5 g, 45.9 mmol) in THF (50mL) was added dropwise over 1 h, resulting in an exothermic reaction.The reaction mixture was refluxed for 5 min and stirred at roomtemperature for 3 h. It was then hydrolyzed with water (100 mL) and a10% aqueous solution of NH₄Cl (50 mL). The organic layer was separatedand the water solution was extracted with EtOAc (100 mL). The organicphases were combined, washed with brine (50 mL), dried over MgSO₄, andconcentrated to afford 1,4-bis(3-hydroxypropyl)benzene (9.0 g,quantitative) as an oil, which was used without further purification forthe next step. ¹H NMR (DMSO-d₆): δ=7.10 (s, 4H), 4.43 (br s, 2H), 3.41(t, J=8.1 Hz, 4H), 2.59 (t, J=8.2 Hz, 4H), 1.71 (m, 2H). ¹³C NMR(DMSO-d₆): δ=139.0, 127.0, 60.0, 34.5, 31.2.

1,4-Bis(3-bromopropyl)benzene (C4)

An emulsion of 1,4-bis(3-hydroxypropyl)benzene (9.0 g, 46.3 mmol) andsodium bromide (24.0 g, 0.23 mol) in deionized water (25 mL) was heatedto reflux, while concentrated sulfuric acid (17 mL) was added dropwiseover 1 h. After the addition, heating under reflux was continued foradditional 3.5 h. The solution was cooled to room temperature, dilutedwith water (40 mL), and extracted with CH₂Cl₂ (2×150 mL). The combinedorganic layers were washed with saturated solution of NaHCO₃ (100 mL),saturated NaCl solution (100 mL) and dried over MgSO₄. The solvent wasevaporated and the residue was purified by column chromatography (silicagel, EtOAc:hexanes, 1:40) to yield 1,4-bis(3-bromopropyl)benzene (11.6g, 78%) as a colorless oil. ¹H NMR (CDCl₃): δ=7.15 (s, 4H), 3.41 (t,J=6.6 Hz, 4H), 2.77 (t, J=7.1 Hz, 4H), 2.18 (m, 4H). ¹³C NMR (CDCl₃):δ=138.3, 128.7, 34.2, 33.4, 33.3. This known compound was prepared by amethod different from the one described in Matsuoka, T., Negi, T.,Otsubo, T., Sakata, Y., Misumi, S. Bull. Chem. Soc., Japan, 1972, 45,1825-1833 and Ruzicka, L.; Buijs, J. B.; Stoll, M. Helv. Chim. Acta1932, 75, 1220.

1,4-Bis(4-ethoxycarboxy-4-methylpentyl)benzene (C5)

Under N₂-atmosphere, to a solution of ethyl isobutyrate (9.0 g, 77.5mmol) in anhydrous THF (300 mL) was added dropwise lithiumdiisopropylamide (1.8 M solution in heptane/THF/EtPh, 46.7 mL, 84.0mmol) at −78° C. After 1 h, a solution of 1,4-bis(3-bromopropyl)benzene(11.6 g, 36.3 mmol) in anhydrous THF (70 mL) was added dropwise,followed by the addition of DMPU (20 mL). The reaction mixture wasallowed to warm to room temperature overnight, then cooled with anice-bath, and hydrolyzed with saturated NH₄Cl solution (100 mL). Water(100 mL) was added and the layers were separated. The aqueous layer wasextracted with ethyl acetate (2×50 mL). The combined organic layers werewashed with saturated NaCl solution (100 mL), dried with MgSO₄, andconcentrated in vacuum. The residue was purified by columnchromatography on silica gel (EtOAc:hexanes, 1:10) to give1,4-bis(4-ethoxycarboxy-4-methylpentyl)benzene (13.3 g, 94%) as acolorless oil. ¹H NMR (CDCl₃): δ=7.09 (s, 4H), 4.11 (q, J=7.1 Hz, 4H),2.57 (m, 4H), 1.57 (m, 8H), 1.24 (t, J=7.1 Hz, 6H), 1.47 (s, 12H). ¹³CNMR (CDCl₃): δ=177.9, 139.6, 128.2, 60.1, 42.0, 40.2, 35.8, 26.8, 25.1,14.2. HRMS calcd for C₂₄H₃₉O₄ (MH⁺): 391.2838. found: 391.2836.

1,4-Bis(4-carboxy-4-methylpentyl)benzene

A solution of 1,4-bis(4-ethoxycarboxy-4-methylpentyl)benzene (13.0 g,33.3 mmol) and potassium hydroxide (85%, 7.0 g, 106 mmol) in ethanol (25mL) and water (15 mL) was heated to reflux for 3.5 h. The reactionmixture was cooled to room temperature, diluted with water (100 mL) andacidified with HCl (2 M solution in water) to pH 1. A precipitate formedimmediately. The mixture was stirred for 1 h, the precipitate wasfiltered and washed with water (2×50 mL). The crude precipitate wasdissolved in methylene chloride (700 mL) and the solution was dried overMgSO₄ overnight. The solvent was evaporated and the residue wasrecrystallized (methylene chloride:hexanes, 1:1) to give1,4-bis(4-carboxy-4-methylpentyl)benzene (9.5 g, 85%, 100% pure by HPLC)as white crystals (Compound III-1). Mp 131° C. (125-126° C., Gleiter,R.; Kramer, R.; Irngartinger, H; Bissinger, C. Synthesis and Propertiesof 4,4,9,9-Tetramethyl[12]paracyclophane-5,6,7,8-tetrone. J. Org. Chem.1992, 57, 252-258). Elemental analysis (C₂₀H₃₀O₄): Calcd for C, 71.82;H, 9.04. found: C, 71.10; H, 9.00. ¹H NMR (CDCl₃): δ=7.07 (br s, 4H),2.55 (m, 4H), 1.59 (m, 8H), 1.18 (s, 12H). ¹³C NMR (CDCl₃): δ=184.9,139.6, 128.1, 42.1, 40.3, 35.8, 26.8, 24.9. This known compound wasprepared by a method modified to the one described in Gleiter, R.;Kramer, R.; Irngartinger, H; Bissinger, C. Synthesis and Properties of4,4,9,9-Tetramethyl[12]paracyclophane-5,6,7,8-tetrone. J. Org. Chem.1992, 57, 252-258.

Example 12: Synthesis of 5,5′-(1,3-Phenylene)bis(2,2-dimethylpentanoicAcid) (Compound I-31)

Dimethyl m-benzene-bis(2,2-dimethyl)pentanoate (D2)

Under Ar-atmosphere, to a solution of ethyl isobutyrate (21.2 g, 24.4mL, 183 mmol) in anhydrous THF (200 mL) was added dropwise lithiumdiisopropylamide (2.0 M in heptane/THF/ethylbenzene, 91.5 mL, 183 mmol)at −78° C. After 1 h, a solution of m-bis(3-bromopropyl)benzene (D1)(prepared according to Schimelpfenig, C. W. J. Org. Chem. 1975, 40,1493-1494 and Effenberger, F.; Kurtz, W. Chem. Ber. 1973, I06, 511-524;26.6 g, 83.1 mmol) in anhydrous THF (50 mL) was added dropwise, followedby the addition of DMPU (25 mL). The reaction mixture was allowed towarm to room temperature overnight, then cooled with an ice-bath, andhydrolyzed with saturated NH₄Cl solution (100 mL). Deionized water (100mL) was added and the layers were separated. The aqueous layer wasextracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with saturated NaCl solution (100 mL), 1 N hydrochloric acid(2×100 mL), saturated NaHCO₃ solution (100 mL), and saturated NaClsolution (100 mL). The combined organic phases were dried over MgSO₄,concentrated in vacuo, and dried in high vacuo. The residue was purifiedby flash chromatography on silica (hexanes/ethyl acetate=95/5) to givediethyl 5,5′-(1,3-phenylene)bis(2,2-dimethylpentanoate) (15.7 g, 48%) asa yellowish oil. ¹H NMR (CDCl₃): 5=7.17 (t, 1H, J=7.0 Hz), 6.97 (m, 3H),4.09 (q, 4H, J=7.3 Hz), 2.55 (m, 4H), 1.56 (m, 8H), 1.22 (t, 6H, J=7.3Hz), 1.15 (s, 12H). ¹³C NMR (CDCl₃): δ=178.02, 142.37, 128.58, 128.32,125.86, 60.31, 42.25, 40.52, 36.48, 27.03, 25.30, 14.39.

5,5′-(1,3-Phenylene)bis(2,2-dimethylpentanoic Acid)

A solution of diethyl 5,5′-(1,3-phenylene)bis(2,2-dimethylpentanoate)(D2) (10.6 g, 27.14 mmol) and potassium hydroxide (85%, 6.3 g, 95.00mmol) in ethanol (20 mL) and water (10 mL) was heated to reflux for 4 h.The reaction mixture was cooled to room temperature, diluted with water(50 mL), and the ethanol was removed under reduced pressure. Theremaining aqueous solution was extracted with dichloromethane (2×50 mL).The aqueous layer was acidified with coned hydrochloric acid (10 mL) topH 1 and extracted with dichloromethane (3×50 mL). The combined organiclayers were washed with saturated NaCl solution (50 mL), dried overMgSO₄, concentrated in vacuo, and dried in high vacuo to give a viscousoil (9.3 g). This oil was crystallized from pentane/dichloromethane (75mL/5 mL) at −5° C. to afford5,5′-(1,3-phenylene)bis(2,2-dimethylpentanoic acid) (4.78 g, 49%, 93.2%pure by HPLC) as a white powder (Compound I-31). Mp 79° C. Elementalanalysis (C₂₀H₃₀O₄): Calcd for C, 71.82; H, 9.04. found: C, 71.71; H,9.22. ¹H NMR (DMSO-d₆): δ=12.2-11.7 (m br, 2H), 7.17 (m, 1H), 6.98 (m,3H), 2.52 (m, 4H), 1.49 (m, 8H), 1.07 (s, 12H). ¹³C NMR (DMSO-d₆):δ=178.86, 141.96, 128.26, 125.69, 41.21, 39.91, 35.68, 26.62, 25.06.HRMS calcd for C₃₀H₃₁O₃ (MH⁺): 335.2222. found: 335.2232.

Example 13: Synthesis of6-[3-(5-Carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoic Acid(Compound I-32)

[1,3-Bis(5,5-dimethyl-6-(tetrahydropyran-2-yloxy)-hexyl]-phenylene (E2)

A solution of n-butyl lithium (38.8 mL, 2.5 M in hexanes/THF/EtPh, 96.9mmol) was added to a mixture of w-xylene (E1) (5.0 g, 47.1 mmol) andpotassium tert-butoxide (5.4 g, 48.1 mmol) in hexanes (100 mL) at roomtemperature. The reaction mixture was heated to reflux for 1 h. A yellowprecipitate was formed. The reaction mixture was cooled to 0° C. and2-(5-bromo-2,2-dimethylpentyloxy)-tetrahydropyran (prepared according toDasseux et al., U.S. Pat. Nos. 6,646,170 and 6,410,802, 30.0 g, 107.5mmol) was added dropwise. The reaction mixture was heated to reflux for20 h. Water (150 mL) was added and the organic phase was separated. Theaqueous solution was extracted with EtOAc (2×100 mL). The organic phaseswere combined, washed with brine (50 mL), and dried over MgSO₄. Thesolvent was evaporated and the residue was purified by columnchromatography (silica gel, EtOAc:hexanes, 1:30) to give[1,3-bis(5,5-dimethyl-6-(tetrahydropyran-2-yloxy)-hexyl]-phenylene (14.8g, 62%, 96.1% pure by HPLC) as an oil. ¹H NMR (CDCl₃): δ=7.17-7.14 (m,1H), 7.00-6.98 (m, 3H), 4.54 (t, J=3.0 Hz, 2H), 3.78-3.86 (m, 2H),3.50-3.45 (m, 2H), 3.47 (d, J=9.1 Hz, 2H) 2.98 (d, J=9.1 Hz, 2H), 2.59(t, J=7.6 Hz, 4H), 1.90-1.28 (m, 24H), 0.89 (s, 12H). ¹³C NMR (CDCl₃):δ=142.8, 128.5, 128.1, 125.6, 99.1, 77.5, 61.8, 39.2, 36.0, 34.2, 32.5,30.7, 25.6, 24.6, 23.7, 19.4. HRMS calcd for C₃₂H₅₄O₄ (M⁺): 501.3943.found: 501.3943.

6-[3-(6-Hydroxy-5,5-dimethylhexyl)-phenyl]-2,2-dimethylhexan-1-ol (E3)

Concentrated, aqueous HCl (20 mL) was added to1,3-bis(5,5-dimethyl-6-(tetrahydropyran-2-yloxy)-hexyl]-phenylene (18.0g, 35.7 mmol) in MeOH (200 mL). The reaction mixture was heated toreflux for 2 h and stirred overnight at room temperature. MeOH wasevaporated in vacuum and the residue was dissolved in methylene chloride(200 mL). The solution was washed with water (100 mL), saturated NaHCO₃solution (100 mL) and brine (100 mL), and dried over MgSO₄. The solventwas evaporated and the residue was purified by column chromatography(silica gel, EtOAc:hexanes, 1:1) to give6-[3-(6-hydroxy-5,5-dimethylhexyl)-phenyl]-2,2-dimethylhexan-1-ol (10.41g, 87%, 86.4% by HPLC) as an oil. ¹H NMR (CDCl₃): δ=7.21-7.19 (m, 1H),7.02-6.99 (3H), 3.32 (s, 4H), 2.62 (t, J=7.8 Hz, 4H), 1.64-1.26 (m,12H), 0.89 (s, 12H). ¹³C NMR (CDCl₃): δ=142.6, 128.5, 128.1, 125.6,71.9, 38.4, 35.8, 35.0, 32.4, 23.7, 23.5. HRMS calcd for C₂₂H₃₈O₄ (M⁺):335.2950, found: 335.2950.

6-[3-(5-Carboxy-5-methylhexyl)-phenyl]-2,2-dimethylhexanoic Acid

Pyridinium dichromate (74.85 g, 199 mmol) was added to a solution of6-[3-(6-hydroxy-5,5-dimethylhexyl)-phenyl]-2,2-dimethylhexan-1-ol (8.5g, 25.4 mmol) in DMF (200 mL) at room temperature. The reaction mixturewas stirred for 30 h, then heated to 40° C. for 10 h. Ethyl acetate (100mL) was added, followed by the addition of water (200 mL) and conedH₂SO₄ (20 mL) under stirring. The organic layer was separated, and theaqueous layer was extracted with EtOAc (3×100 mL). The combined organicsolutions were washed with water (100 mL), saturated NaHCO₃ solution(100 mL) and brine (2×100 mL) and dried over MgSO₄. The solvent wasevaporated and the residue was purified by column chromatography (silicagel, EtOAc:hexanes, 1:1). The obtained oil was stirred in Et₂O:hexanes(1:10, 50 mL) for 3 h and the precipitated solid product was filtered(7.2 g, 78%, 96.1% by HPLC) (Compound I-32). Mp 99-101° C. Elementalanalysis (C₂₂H₃₄O₄): Calcd for C, 72.89; H, 9.45. found: C, 73.02; H,9.57. ¹H NMR (CDCl₃): δ=7.19-7.16 (m, 1H), 6.99-6.94 (m, 3H), 2.58 (t,J=7.1 Hz, 4H), 1.63-1.56 (m, 8H), 1.32-1.22 (m, 4H), 1.18 (s, 12H). ¹³CNMR (CDCl₃): δ=185.5, 142.2, 128.6, 128.3, 126.0, 42.0, 40.8, 35.7,31.0, 25.1, 24.4. HRMS calcd for C₂₂H₃₅O₄ (MH⁺): 363.2535. found:363.2530.

Example 14: Synthesis of 5,5′-(1,2-Phenylene)bis(2,2-dimethylpentanoicAcid) (Compound I-61)

3-[2-(3-Hydroxypropyl)-phenyl]-propanol (F2)

Under Ar-atmosphere, to a stirred suspension of lithium aluminum hydride(3.0 g, 78.2 mmol) in anhydrous THF (100 mL) was added dropwise asolution of 3-[2-(2-ethoxycarbonylethyl)-phenyl]-propionic acid ethylester (prepared according to Fakhri, S. A.; Behrooz, Y. H. Tetrahedron2000, 56, 8301-8308; 14.5 g, 52.1 mmol) in THF (100 mL) over 50 min atroom temperature. The mixture was stirred for 2 h, then cooled with anice bath, and carefully hydrolyzed by dropwise addition of deionizedwater (100 mL). The hydrolysis was completed by dropwise addition of 10%sulfuric acid at room temperature and stirring overnight. The mixturewas extracted with dichloromethane (200 mL, 2×100 mL). The combinedorganic layers were washed with saturated sodium chloride solution (100mL), dried over MgSO₄, concentrated in vacuo, and dried in high vacuo togive 3-[2-(3-hydroxypropyl)-phenyl]-propanol (8.6 g, 85%, 87.9% pure byGC) as a turbid oil, which was used without further purification for thenext step. ¹H NMR (CDCl₃): δ=7.20-7.05 (m, 4H), 3.67 (t, 4H, J=6.1 Hz),3.50-3.20 (m br., 2H), 2.72 (m, 4H), 1.82 (m, 4H). ¹³C NMR (CDCl₃):δ=139.98, 129.43, 126.24, 62.35, 34.36, 29.01. HRMS calcd for C₁₂H₁₉O₂(MH⁺): 195.1385. found: 195.1388. This known compound was prepared by amethod different than the one described in Uenaka, M.; Kubota, B. Bull.Chem. Soc. Jpn. 1936, II, 19-26.

1,2-Bis-(3-bromopropyl)-benzene (F3)

A mixture of 3-[2-(3-hydroxypropyl)-phenyl]-propanol (8.6 g, 44.27mmol), sodium bromide (18.6 g, 180.62 mmol) and water (16 mL) was heatedat reflux while concentrated sulfuric acid (13.3 mL) was added dropwiseover 20 min. The solution was heated for additional 75 min at reflux,then cooled to room temperature, and diluted with deionized water (200mL). The mixture was extracted with dichloromethane (3×100 mL) and thecombined organic layers were successively washed with water (100 mL),saturated sodium bicarbonate solution (100 mL), 10% aqueous sodiumthiosulfate solution (200 mL), and saturated sodium chloride solution(100 mL). The organic layer was dried over MgSO₄, concentrated in vacuo,and dried in high vacuo to give the crude product (11.2 g) as a brownoil. The crude material was purified by flash chromatography (silica,hexanes, then hexanes/ethyl acetate=90/10), affording1,2-bis-(3-bromopropyl)-benzene (8.25 g, 58%, 95.9% pure by GC) as aviscous, yellow oil. ¹H NMR (CDCl₃): δ=7.16 (s, 4H), 3.33 (t, 4H, J=6.3Hz), 2.79 (m, 4H), 2.12 (m, 4H). ¹³C NMR (CDCl₃): δ=138.69, 129.69,126.66, 34.14, 33.62, 30.99. HRMS calcd for C₁₂H₁₆Br₂ (M⁺): 317.9619.found: 317.9624. This known compound was prepared by a method differentthan the one described in Uenaka, M.; Kubota, B. Bull. Chem. Soc. Jpn.1936, 77, 19-26.

5-[2-(4-Ethoxycarbonyl-4-methylpentyl)-phenyl]-2,2-dimethylpentanoicAcid Ethyl Ester (F4)

Under Ar-atmosphere, to a solution of ethyl isobutyrate (8.7 g, 10.0 mL,74.98 mmol) in anhydrous THF (100 mL) was added dropwise over 15 min asolution of lithium diisopropylamide (2.0 M in heptane/THF/ethylbenzene, 41.2 mL, 82.48 mmol) at −78° C. After 85 min, a solution of1,2-bis-(3-bromopropyl)-benzene (8.0 g, 74.98 mmol) in anhydrous THF (25mL) was added dropwise over 10 min, followed by dropwise addition ofDMPU (15 mL). The mixture was stirred at −78° C. for an additional hour,then allowed to slowly warm to room temperature over the next 2 h andstirred overnight. The reaction mixture was cooled with an ice-bath andhydrolyzed by addition of saturated NH₄Cl solution (100 mL) anddeionized water (100 mL). The layers were separated, and the aqueouslayer was extracted with ethyl acetate (3×100 mL). The combined organiclayers were washed with water (100 mL), 1 N hydrochloric acid (100 mL),water (100 mL), and saturated sodium chloride solution (100 mL). Theorganic phase was then dried over MgSO₄ and concentrated in vacuo toyield the crude product (14.0 g) as a reddish oil. Purification by flashchromatography (silica, hexane/ethyl acetate=95/5) afforded5-[2-(4-ethoxycarbonyl-4-methylpentyl)-phenyl]-2,2-dimethylpentanoicacid ethyl ester (8.2 g, 84%, 79% pure by GC) as a slightly yellowishoil. ¹H NMR (CDCl₃): δ=7.11 (s, 4H), 4.10 (q, 4H, J=7.0 Hz), 2.56 (t,4H, J=7.6 Hz), 1.68-1.42 (m, 8H), 1.23 (t, 6H, J=7.0 Hz), 1.16 (s, 16H).¹³C NMR(CDCl₃): δ=177.95, 140.01, 129.12, 126.04, 60.34, 42.26, 40.79,33.11, 26.75, 25.29, 14.41. HRMS calcd for C₂₄H₃₉O₄ (MH⁺): 391.2848.found: 391.2846.

5,5′-(1,2-phenylene)bis(2,2-dimethylpentanoic Acid) (or5-[2-(4-carboxy-4-methylpentyl)-phenyl]-2,2-dimethylpentanoic Acid)

A solution of5-[2-(4-ethoxycarbonyl-4-methylpentyl)-phenyl]-2,2-dimethylpentanoicacid ethyl ester (8.3 g, 21.25 mmol) and potassium hydroxide (>85%, 4.91g, 74.38 mmol) in ethanol (20 mL) and water (10 mL) was heated at refluxfor 4 h. After cooling to room temperature, the mixture was diluted withwater (50 mL) and concentrated in vacuo to ca. 60 mL volume. Thisaqueous solution was extracted with dichloromethane (2×30 mL) and thenacidified with 1 N hydrochloric acid (8 mL) to pH 1. The aqueous layerwas extracted with dichloromethane (3×30 mL). The combined organicextracts were washed with saturated NaCl solution (30 mL), dried overMgSO₄, and concentrated in vacuo to furnish the crude product (5.50 g)as a white solid/viscous oil. The crude material was crystallized fromheptane/dichloromethane at −5° C. to afford tiny white crystals thatwere washed with cold heptane (10 mL) and dried in high vacuo (5.05 g,71%, 98.3% pure by HPLC) (Compound 1-61). Mp 108-109° C. Elementalanalysis (C₂₀H₃₀O₄): Calcd for C, 71.82; H, 9.04. found: C, 71.14; H,9.06. ¹H NMR (DMSO-d₆): δ=12.7-11.5 (m br, 2H), 7.11 (s, 4H), 2.55 (t,4H, J=13 Hz), 1.62-1.38 (m, 8H), 1.09 (s, 12H). ¹³C NMR (DMSO-d₆):δ=178.83, 139.69, 128.98, 125.89, 41.25, 40.20, 32.49, 26.57, 25.04.HRMS calcd for C₂₀H₃₁O₄ (MH⁺): 335.2222. found: 335.2232.

Biological Assays Example 15: Anti-Proliferative Effects of CompoundsI-32, I-61, I-1, and III-1 in Hep3B and Hepa1-6 Liver Cancer Cells

Human liver cancer cells Hep3B and murine liver cancer cells Hepa1-6,respectively, were seeded at a cell density of 3000 cells/well in96-well plates using either Eagle's Minimum Essential Medium (Corning)for Hep3B or Dulbecco's Modified Eagle's Medium (DMEM) High Glucose(Gibco) for Hepa1-6 cells, supplemented with 10% fetal bovine serum(FBS, Gibco) and 1% Antibiotic-Antimycotic solution (Thermo-FisherScientific). The next day, the cells were treated with 0 (vehiclecontrol), 0.1, 0.5, 1, 5, 10, 30, 50 or 100 μM Compound I-32, I-61, I-1,or III-1 (final concentration of DMSO 0.1%) and were allowed to grow for72 hours at 37° C. On day 5, 10 μl of PrestoBlue™ Cell Viability Reagent(Invitrogen) was added to each well and the plate was incubated at 37°C. for an additional 1-2 hours. After incubation, fluorescence signalwas measured with an excitation/emission wavelength of 560/590 nm usinga SpectraMax M5 Microplate Reader (Molecular Devices).

The effects of Compounds I-32, I-61, I-1, and III-1 on cellproliferation in Hepa1-6 cells as a percent of vehicle control (DMSO,0.1% final concentration) are shown in FIGS. 2A-2D, respectively (n=4replicates, single experiment, error bar represents the standarddeviation). The effects of the Compounds I-32, I-61, I-1, and III-1 onHep3B cell proliferation as a percent of vehicle control (DMSO, 0.1%final concentration) are shown in FIGS. 3A-3D, respectively (n=5, singleexperiment, error bar represents the standard deviation).

Example 16: Anti-Clonogenic Effects of Compounds I-32, I-61, I-1, andIII-1 in Hep3B and Hep1-6 Liver Cancer Cells

Liver cancer cell lines Hep3B (human) and Hepa1-6 (murine) weremaintained in either Eagle's Minimum Essential Medium (Corning) forHep3B cells or High Glucose DMEM (Gibco) for Hepa1-6 cells, supplementedwith 10% FBS (Gibco) and 1% Antibiotic-Antimycotic (Thermo-FisherScientific). Each cell line was seeded at 1000 cells/well in 12-wellplates. The next day, the media were replaced, and cells were treatedwith 0 (vehicle control, 0.1% DMSO), 1, 5, 10, 30, 50, or 100 μMCompound I-32, I-61, I-1, or III-1 (final concentration of DMSO 0.1%)for 7 days. On day 9, the media were removed, and cells were fixed with10% formalin (500 μl) for 10 minutes at room temperature, washed with IXPBS and stained with crystal violet. After 10 minutes the excess stainwas removed by rinsing three times with tap water. The plates wereallowed to dry overnight, then the number of colonies (>50 cells) ineach well were counted using light microscopy as described previously byVilliani L. A., et al.

The effects of Compounds I-32, I-61, I-1, and III-1 on clonogenicity inHepa1-6 cells as a percent of vehicle control (DMSO, 0.1% finalconcentration) are shown in FIGS. 4A-4D, respectively (n=2, error barsrepresent the standard deviation). The effects of Compounds I-32, I-61,I-1, and III-1 on clonogenicity in Hep3B cells as a percent of vehiclecontrol (DMSO, 0.1% final concentration) are shown in FIGS. 5A-5D,respectively (n=2, error bars represent the standard deviation).

Table 1 summarizes the biology results from Examples 15-17. ND=notdetermined.

TABLE 1 Effects on de Novo Lipogenesis (DNL), Clonogenicity and CancerCell Proliferation of Illustrative Compounds of the Invention in Human(h) and Murine (m) cells (IC₅₀ or % Proliferation Reduction,respectively). Compound Compound Compound Compound Assay Cell Line I-1I-32 I-61 III-1 IC₅₀ (μM) DNL primary 12.1 8.3 ND ND hepatocytes (m)Clonogenicity Hepa1-6 (m) 55.6 52.3 73.4 61.0 Clonogenicity Hep3B (h)53.9 41.7 57.3 55.6 % reduction vs control at 100 μM Mean (StandardDeviation) Cancer Cell Hepa1-6 (m) 25.9 (5.7) 18.6 (3.1) 21.8 (8.9) 15.7(6.7) Proliferation Cancer Cell Hep3B (h) 41.8 (8.4) 30.8 (2.6) 35.7(5.8) 29.7 (6.2) Proliferation

Example 17: Synergistic Effect of Illustrative Compounds of theInvention with Sorafenib or Lenvatinib

Combination studies were undertaken with the compounds of the inventionto determine potential synergy of sorafenib or lenvatinib in thepresence of compound I-32 or compound I-61. In a separate experiment,the IC₅₀ for inhibition of proliferation by sorafenib in the absence ofa compound of the invention and lenvatinib in the absence of a compoundof the invention was determined to be 3 μM and 0.5 μM, respectively, inHep3B cells and 5 μM and 30 μM, respectively, in Hepa1-6 cells (data notshown).

Hep3B (supplied by ATCC) or Hepa1-6 (supplied by ATCC) cells were seededin 96-well plates at a density of 500 cells/well with complete media. Onday 2, media in each well was aspirated and replaced with 100 μl offresh complete media and cells were treated with sorafenib or lenvatinibin the presence of or without the compounds of the invention, in aconcentration dependent manner (Compound I-32 (100 μM) or Compound I-61(100 μM) either alone or in combination with sorafenib (3 μM) orlenvatinib (0.5 μM)). Then, cells were incubated in an incubator for 72h. On day 5, 10 μl of presto blue (Invitrogen, cat #A13261) cellviability reagent was added in each 96-well plate and incubated at 37°C. for 1-2 h. After incubation, fluorescence was measured with anexcitation/emission wavelength of 560/590 nm. Results were indicated asmean±standard deviation (SD). All bar diagrams and line graphs wereprepared using Graph Pad Prism 8 software. Proliferation IC₅₀ valueswere calculated using a non-linear regression model in Graph pad Prism8. For each cell type, combination treatment showed a decrease in cellproliferation when compared to sorafenib or lenvatinib alone. Results inHep3B cells are presented in FIGS. 6A-6B and results in Hepa1-6 cellsare presented in FIGS. 7A-7B.

Sorafenib and lenvatinib have the following structure:

Since additional inhibition of cell proliferation was observed in thecombination studies, the results were analyzed using CompuSyn software(provided by ComboSyn Inc.) to examine if there was a synergistic oradditive effect on the antiproliferative activity. FIGS. 8A-8Ddemonstrate that both Compounds I-32 and 1-61 showed synergisticinhibition in the presence of sorafenib or lenvatinib.

What is claimed is:
 1. A composition comprising: (i) an effective amountof a compound having the structure:

 or a pharmaceutically acceptable salt or solvate thereof; (ii)sorafenib or lenvatinib; and (iii) a pharmaceutically acceptable carrieror vehicle.